N-Alkyl, N-Alkenyl, N-Alkynyl, N-Aryl and N-fused bicyclo or tricyclo thienyl-, furyl-,and Pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin

ABSTRACT

N-alkyl, N-alkenyl, N-alkynyl, N-aryl and N-fused bicyclo or tricyclo thienyl-, furyl- and pyrrolyl-sulfonamides and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, (phenyl) and (phenoxy)thienylsulfonamides, (phenyl) and (phenoxy)furylsulfonamides, and (phenyl) and (phenoxy)pyrrolylsulfonamides and methods of using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or prodrugs thereof that inhibit or increase the activity of endothelin are also provided.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.08/721,183 to Chan et al., filed Sep. 27, 1996, entitled, “THIENYL-,FURYL- AND PYRROLYL SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATETHE ACTIVITY OF ENDOTHELIN issued Oct. 5, 1999 as U.S. Pat. No.5,962,490”. The subject matter of the above-referenced application isincorporated herein in its entirety.

U.S. application Ser. No. 08/721,183 is a continuation-in-part ofInternational Patent Application No. PCT/US96/04759, filed Apr. 4, 1996,entitled THIENYL-, FURYL- PYRROLYL- AND BIPHENYLSULFONAMIDES ANDDERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”, publishedOct. 10, 1996 as International Patent Application Publication No. WO96/31492; is also a continuation-in-part of U.S. application Ser. No.08/477,223, now U.S. Pat. No. 5,594,021, filed Jun. 6, 1995, entitled,“THIENYL-, FURYL- AND PYRROLYL SULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”; is also a continuation-in-part ofU.S. application Ser. No. 08/417,075, filed Apr. 4, 1995, entitled,“THIENYL-, FURYL- AND PYRROLYL SULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”, now abandoned; is also acontinuation-in-part of U.S. application Ser. No. 08/247,072, now U.S.Pat. No. 5,571,821, to Chan et al., filed May 20, 1994, entitled“SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OFENDOTHELIN”; is also a continuation-in-part of U.S. application Ser. No.08/222,287, now U.S. Pat. No. 5,591,761, to Chan et al., filed Apr. 5,1994, entitled “THIOPHENYL-, FURYL- AND PYRROLYL-SULFONAMIDES ANDDERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”; each ofthese applications is a continuation-in-part of U.S. application Ser.No. 08/142,552, now U.S. Pat. No. 5,514,691, to Chan et al., filed Oct.21, 1993, entitled “N-(4-HALO-ISOXAZOLYL)-SULFONAMIDES AND DERIVATIVESTHEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELUN”; U.S. application Ser.No. 08/142,159, now U.S. Pat. No. 5,464,853, to Chan et al., filed Oct.21, 1993, entitled “N-(5-ISOXAZOLYL)BIPHENYLSULFONA-MIDES,N-(3-ISOXAZOLYL)BIPHENYLSULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”; and U.S. application Ser. No.08/142,631 to Chan et al., filed Oct. 21, 1993,“N-(5-ISOXAZOLYL)-BENZENE-SULFONAMIDES,N-(3-ISOXAZOLYL)-BENZENESULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”, now abandoned. International PCTapplication No. PCT/US96/04759 is a continuation-in-part of U.S.application Ser. No. 08/477,223. U.S. application Ser. No. 08/477,223 isa continuation-in-part of U.S. application Ser. No. 08/417,075. Each ofU.S. application Ser. Nos. 08/477,223, 08/417,075 and 08/416,119 filedApr. 4, 1995 is in turn a continuation-in-part of U.S. application Ser.No. 08/247,072; U.S. application Ser. No. 08/222,287; U.S. applicationSer. No. 08/142,552, now U.S. Pat. No. 5,514,691; U.S. application Ser.No. 08/142,159, now U.S. Pat. No. 5,464,853; U.S. application Ser. No.08/142,631, now abandoned; U.S. application Ser. No. 08/100,565, nowabandoned; U.S. application Ser. No. 08/100,125, now abandoned; and U.S.application Ser. No. 08/065,202, to Chan, filed May 20, 1993, entitled“SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OFENDOTHELIN”, now abandoned.

U.S. application Ser. No. 08/417,075 is a continuation-in-part of U.S.application Ser. No. 08/247,072, which is a continuation-in-part of U.S.application Ser. No. 08/222,287. U.S. application Ser. No. 08/416,199,U.S. application Ser. No. 08/247,072 and U.S. application Ser. No.08/222,287 are each a continuation-in-part of the followingapplications: U.S. application Ser. No. 08/142,552, now U.S. Pat. No.5,514,691; U.S. application Ser. No. 08/142,159, now U.S. Pat. No.5,464,853; U.S. application Ser. No. 08/142,631 to Chan et al., filedOct. 21, 1993, “N-(5-ISOXAZOLYL)-BENZENESULFONAMIDES,N-(3-ISOXAZOLYL)-BENZENESULFONAMIDES AND DERIVATIVES THEREOF THATMODULATE THE ACTIVITY OF ENDOTHELIN”; U.S. application Ser. No.08/100,565 to Chan et al., filed Jul. 30, 1993, entitled“N-(5-ISOXAZOLYL)-SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THEACTIVITY OF ENDOTHELIN”; U.S. application Ser. No. 08/100,125 to Chan etal., filed Jul. 30, 1993, entitled “N-(3-ISOXAZOLYL)-SULFONAMIDES ANDDERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELlIN, and U.S.application Ser. No. 08/065,202, to Chan, filed May 20, 1993, entitled“SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OFENDOTHELIN”.

U.S. application Ser. No. 08/416,199 is a continuation-in-part of U.S.application Ser. No. 08/247,072; U.S. application Ser. No. 08/222,287;U.S. application Ser. No. 08/142,159, now U.S. Pat. No. 5,464,853; U.S.application Ser. No. 08/142,552, now U.S. Pat. No. 5,514,691; U.S.application Ser. No. 081100,565, now abandoned; U.S. application Ser.No. 08/100,125, now abandoned; and U.S. application Ser. No. 08/065,202,now abandoned.

U.S. application Ser. Nos. 08/142,159, 08/142,552, 08/142,631 arecontinuation-in-part applications of U.S. Application Ser. Nos.08/100,565, 08/100,125 and 08/065,202, and U.S. application Ser. Nos.08/100,565 and 08/100,125 are continuation-in-part applications of U.S.application Ser. No. 08/065,202.

The subject matter of International PCT application No. PCT/US96/0475and each of U.S. application Ser. Nos. 08/721,183, 08/477,223,08/417,075, 08/416,199, 08/247,072, 08/222,287, 08/142,159, 08/142,552,08/142,631, 08/100,565, 08/100,125 and 08/065,202 is incorporated hereinin its entirety.

FIELD OF THE INVENTION

The present invention relates to the compounds that modulate theactivity of the endothelin family of peptides. In particular, theinvention relates to the use of sulfonamides and sulfonamide pro-drugsas endothelin agonists and antagonists.

BACKGROUND OF THE INVENTION

The vascular endothelium releases a variety of vasoactive substances,including the endothelium-derived vasoconstrictor peptide, endothelin(ET) (see, e.g., Vanhoutte et al. (1986) Annual Rev. Physiol. 48:307-320; Furchgott and Zawadski (1980) Nature 288: 373-376). Endothelin,which was originally identified in the culture supernatant of porcineaortic endothelial cells (see, Yanagisawa et al. (1988) Nature 332:411-415), is a potent twenty-one amino acid peptide vasoconstrictor. Itis the most potent vasopressor known and is produced by numerous celltypes, including the cells of the endothelium, trachea, kidney andbrain. Endothelin is synthesized as a two hundred and three amino acidprecursor preproendothelin that contains a signal sequence which iscleaved by an endogenous protease to produce a thirty-eight (human) orthirty-nine (porcine) amino acid peptide. This intermediate, referred toas big endothelin, is processed in vivo to the mature biologicallyactive form by a putative endothelin-converting enzyme (ECE) thatappears to be a metal-dependent neutral protease (see, e.g., Kashiwabaraet al. (1989) FEBS Lttrs. 247: 337-340). Cleavage is required forinduction of physiological responses (see, e.g., von Geldern et al.(1991) Peptide Res. 4: 32-35). In porcine aortic endothelial cells, thethirty-nine amino acid intermediate, big endothelin, is hydrolyzed atthe Trp²¹-Val²² bond to generate endothelin-1 and a C-terminal fragment.A similar cleavage occurs in human cells from a thirty-eight amino acidintermediate. Three distinct endothelin isopeptides, endothelin-1,endothelin-2 and endothelin-3, that exhibit potent vasoconstrictoractivity have been identified.

The family of three isopeptides endothelin-1, endothelin-2 andendothelin-3 are encoded by a family of three genes (see, Inoue et al.(1989) Proc. Natl. Acad. Sci. USA 86: 2863-2867; see, also Saida et al.(1989) J. Biol. Chem. 264: 14613-14616). The nucleotide sequences of thethree human genes are highly conserved within the region encoding themature 21 amino acid peptides and the C-terminal portions of thepeptides are identical. Endothelin-2 is (Trp⁶,Leu⁷) endothelin-1 andendothelin-3 is (Thr²,Phe⁴,Thr⁵,Tyr⁶,Lys⁷,Tyr¹⁴) endothelin-1. Thesepeptides are, thus, highly conserved at the C-terminal ends. Release ofendothelins from cultured endothelial cells is modulated by a variety ofchemical and physical stimuli and appears to be regulated at the levelof transcription and/or translation. Expression of the gene encodingendothelin-1 is increased by chemical stimuli, including adrenaline,thrombin and Ca²⁺ ionophore. The production and release of endothelinfrom the endothelium is stimulated by angiotensin II, vasopressin,endotoxin, cyclosporine and other factors (see, Brooks et al. (1991)Eur. J. Pharm. 194:115-117), and is inhibited by nitric oxide.Endothelial cells appear to secrete short-lived endothelium-derivedrelaxing factors (EDRF), including nitric oxide or a related substance(Palmer et al. (1987) Nature 327: 524-526), when stimulated byvasoactive agents, such as acetylcholine and bradykinin.Endothelin-induced vasoconstriction is also attenuated by atrialnatriuretic peptide (ANP).

The endothelin peptides exhibit numerous biological activities in vitroand in vivo. Endothelin provokes a strong and sustained vasoconstrictionin vivo in rats and in isolated vascular smooth muscle preparations; italso provokes the release of eicosanoids and endothelium-derivedrelaxing factor (EDRF) from perfused vascular beds. Intravenousadministration of endothelin-1 and in vitro addition to vascular andother smooth muscle tissues produce long-lasting pressor effects andcontraction, respectively (see, eg., Bolger et al. (1991) Can. J.Physiol. Pharmacol. 69: 406-413). in isolated vascular strips, forexample, endothelin-1 is a potent (EC₅₀=4×10⁻¹⁰ M), slow acting, butpersistent, contractile agent. In vivo, a single dose elevates bloodpressure in about twenty to thirty minutes. Endothelin-inducedvasoconstriction is not affected by antagonists to knownneurotransmitters or hormonal factors, but is abolished by calciumchannel antagonists. The effect of calcium channel antagonists, however,is most likely the result of inhibition of calcium influx, since calciuminflux appears to be required for the long-lasting contractile responseto endothelin.

Endothelin also mediates renin release, stimulates ANP release andinduces a positive inotropic action in guinea pig atria. In the lung,endothelin-1 acts as a potent bronchoconstrictor (Maggi et al. (1989)Eur. J. Pharmacol. 160: 179-182). Endothelin increases renal vascularresistance, decreases renal blood flow, and decreases glomerularfiltrate rate. It is a potent mitogen for glomerular mesangial cells andinvokes the phosphoinoside cascade in such cells (Simonson et al. (1990)J. Clin. Invest. 85: 790-797).

There are specific high affinity binding sites (dissociation constantsin the range of 2-6×10⁻¹⁰ M) for the endothelins in the vascular systemand in other tissues, including the intestine, heart, lungs, kidneys,spleen, adrenal glands and brain. Binding is not inhibited bycatecholamines, vasoactive peptides, neurotoxins or calcium channelantagonists. Endothelin binds and interacts with receptor sites that aredistinct from other autonomic receptors and voltage dependent calciumchannels. Competitive binding studies indicate that there are multipleclasses of receptors with different affinities for the endothelinisopeptides. The sarafotoxins, a group of peptide toxins from the venomof the snake Atractaspis eingadensis that cause severe coronaryvasospasm in snake bite victims, have structural and functional homologyto endothelin-1 and bind competitively to the same cardiac membranereceptors (Kloog et al. (1989) Trends Pharmacol. Sci. 10: 212-214).

Two distinct endothelin receptors, designated ET_(A) and ET_(B), havebeen identified and DNA clones encoding each receptor have been isolated(Arai et al. (1990) Nature 348: 730-732; Sakurai et al. (1990) Nature348: 732-735). Based on the amino acid sequences of the proteins encodedby the cloned DNA, it appears that each receptor contains seven membranespanning domains and exhibits structural similarity to G-protein-coupledmembrane proteins. Messenger RNA encoding both receptors has beendetected in a variety of tissues, including heart, lung, kidney andbrain. The distribution of receptor subtypes is tissue specific (Martinet al. (1989) Biochem. Biophys. Res. Commun. 162: 130-137). ET_(A)receptors appear to be selective for endothelin-1 and are predominant incardiovascular tissues. ET_(B) receptors are predominant innoncardiovascular tissues, including the central nervous system andkidney, and interact with the three endothelin isopeptides (Sakurai etal. (1990) Nature 348: 732-734). In addition, ET_(A) receptors occur onvascular smooth muscle, are linked to vasoconstriction and have beenassociated with cardiovascular, renal and central nervous systemdiseases; whereas ET_(B) receptors are located on the vascularendothelium, linked to vasodilation (Takayanagi et al. (1991) FEBSLttrs. 28:2: 103-106) and have been associated with bronchoconstrictivedisorders.

By virtue of the distribution of receptor types and the differentialaffinity of each isopeptide for each receptor type, the activity of theendothelin isopeptides varies in different tissues. For example,endothelin-1 inhibits ¹²⁵I-labelled endothelin-1 binding incardiovascular tissues forty to seven hundred times more potently thanendothelin-3. ¹²⁵I-labelled endothelin-1 binding in non-cardiovasculartissues, such as kidney, adrenal gland, and cerebellum, is inhibited tothe same extent by endothelin-1 and endothelin-3, which indicates thatET_(A) receptors predominate in cardiovascular tissues and ET_(B)receptors predominate in non-cardiovascular tissues.

Endothelin plasma levels are elevated in certain disease states (see,e.g., International PCT Application WO 94/27979, and U.S. Pat. No.5,382,569, which disclosures are herein incorporated in their entiretyby reference). Endothelin-1 plasma levels in healthy individuals, asmeasured by radioimmunoassay (RIA), are about 0.26-5 pg/ml. Blood levelsof endothelin-1 and its precursor, big endothelin, are elevated inshock, myocardial infarction, vasospastic angina, kidney failure and avariety of connective tissue disorders. In patients undergoinghemodialysis or kidney transplantation or suffering from cardiogenicshock, myocardial infarction or pulmonary hypertension levels as high as35 pg/ml have been observed (see, Stewart et al. (1991) Annals InternalMed. 114: 464-469). Because endothelin is likely to be a local, ratherthan a systemic, regulating factor, it is probable that the levels ofendothelin at the endothelium/smooth muscle interface are much higherthan circulating levels.

Elevated levels of endothelin have also been measured in patientssuffering from ischemic heart disease (Yasuda et al. (1990) Amer. HeartJ. 119:801-806, Ray et al. (1992) Br. Heart J. 67:383-386). Circulatingand tissue endothelin immunoreactivity is increased more than twofold inpatients with advanced atherosclerosis (Lerman et al. (1991) New Engl.J. Med. 325:997-1001). Increased endothelin immunoreactivity has alsobeen associated with Buerger's disease (Kanno et al. (1990) J. Amer.Med. Assoc. 264:2868) and Raynaud's phenomenon (Zamora et al. (1990)Lancet 336 1144-1147). Increased circulating endothelin levels wereobserved in patients who underwent percutaneous transluminal coronaryangioplasty (PTCA) (Tahara et al. (1991) Metab. Clin. Exp. 40:1235-1237;Sanjay et al. (1991) Circulation 84(Suppl. 4):726), and in individuals(Miyauchi et al. (1992) Jpn. J. Pharmacol. 58:279P; Stewart et al.(1991) Ann.Internal Medicine 114:464-469) with pulmonary hypertension.Thus, there is clinical human data supporting the correlation betweenincreased endothelin levels and numerous disease states.

Endothelin Agonists and Antagonists

Because endothelin is associated with certain disease states and isimplicated in numerous physiological effects, compounds that caninterfere with or potentiate endothelin-associated activities, such asendothelin-receptor interaction and vasoconstrictor activity, are ofinterest. Compounds that exhibit endothelin antagonistic activity havebeen identified. For example, a fermentation product of Streptomycesmisakiensis, designated BE-18257B, has been identified as an ET_(A)receptor antagonist. BE-18257B is a cyclic pentapeptide,cyclo(D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp), which inhibits ¹²⁵I-labelledendothelin-1 binding in cardiovascular tissues in aconcentration-dependent manner (IC₅₀ 1.4 μM in aortic smooth muscle, 0.8μM in ventricle membranes and 0.5 μM in cultured aortic smooth musclecells), but fails to inhibit binding to receptors in tissues in whichET_(B) receptors predominate at concentrations up to 100 μM. Cyclicpentapeptides related to BE-18257B, such ascyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123), have been synthesized andshown to exhibit activity as ET_(A) receptor antagonists (see, U.S. Pat.No. 5,114,918 to Ishikawa et al.; see, also, EP A1 0 436 189 to BANYUPHARMACEUTICAL CO., LTD (Oct. 7, 1991)). Studies that measure theinhibition by these cyclic peptides of endothelin-1 binding toendothelin-specific receptors indicate that these cyclic peptides bindpreferentially to ET_(A) receptors. Other peptide and non-peptidicET_(A) antagonists have been identified (see, e.g., 5,352,800,5,334,598, 5,352,659, 5,248,807, 5,240,910, 5,198,548, 5,187,195,5,082,838). These include other cyclic pentapeptides, acyltripeptides,hexapeptide analogs, certain anthraquinone derivatives, indanecarboxylicacids, certain N-pyriminylbenzenesulfonamides, certainbenzenesulfonamides, and certain naphthalenesulfonamides (Nakajima etal. (1991) J. Antibiot. 44:1348-1356; Miyata et al. (1992) J. Antibiot.45:74-8; Ishikawa et al. (1992) J.Med. Chem. 35:2139-2142; U.S. Pat. No.5,114,918 to Ishikawa et al.; EP A1 0 569 193; EP A1 0 558 258; EP A1 0436 189 to BANYU PHARMACEUTICAL CO., LTD (Oct. 7, 1991); Canadian PatentApplication 2,067,288; Canadian Patent Application 2,071,193; U.S. Pat.No. 5,208,243; U.S. Pat. No. 5,270,313; U.S. Pat. No. 5,464,853 to Chanet al.; Cody et al. (1993) Med. Chem. Res. 3:154-162; Miyata et al.(1992) J. Antibiot 45:1041-1046; Miyata et al. (1992) J. Antibiot45:1029-1040, Fujimoto et al. (1992) FEBS Lett. 305:41-44; Oshashi etal. (1002) J. Antibiot 45:1684-1685; EP A1 0 496 452; Clozel et al.(1993) Nature 365:759-761; International Patent Application WO93/08799;Nishikibe et al. (1993) Life Sci. 52:717-724; and Benigni et al. (1993)Kidney Int. 44:440-444). In general, the identified compounds haveactivities in vitro assays as ET_(A) antagonists at concentrations onthe order of about 50-100 μM or less. A number of such compounds havealso been shown to possess activity in vivo animal models. Very fewselective ET_(B) antagonists have been identified.

Endothelin Antagonists and Agonists as Therapeutic Agents

It has been recognized that compounds that exhibit activity at IC₅₀ orEC₅₀ concentrations on the order of 10⁻⁴ or lower in standard in vitroassays that assess endothelin antagonist or agonist activity havepharmiacological utility (see, e.g, U.S. Pat. Nos. 5,352,800, 5,334,598,5,352,659, 5,248,807, 5,240,910, 5,198,548, 5,187,195, 5,082,83,3). Byvirtue of this activity, such compounds are considered to be useful forthe treatment of hypertension such as peripheral circulatory failure,heart disease such as angina pectoris, cardiomyopathy, arteriosclerosis,myocardial infarction, pulmonary hypertension, vasospasm, vascularrestenosis, Raynaud's disease, cerebral stroke such as cerebral arterialspasm, cerebral ischemia, late phase cerebral spasm after subarachnoidhemorrhage, asthma, bronchoconstriction, renal failure, particularlypost-ischemic renal failure, cyclosporine nephrotoxicity such as acuterenal failure, colitis, as well as other inflammatory diseases,endotoxic shock caused by or associated with endothelin, and otherdiseases in which endothelin has been implicated.

In view of the numerous physiological effects of endothelin and itsassociation with certain diseases, endothelin is believed to play acritical role in these pathophysiological conditions (see, e.g., Saitoet al. (1990) Hypertension 15: 734-738; Tomita et al. (1989) N. Engl. J.Med. 321: 1127; Kurihara et al. (1989) J. Cardiovasc. Pharmacol.13(Suppl. 5): S13-S17; Doherty (1992) J. Med. Chem. 35: 1493-1508; Morelet al. (1989) Eur. J. Pharmacol. 167: 427-428). More detailed knowledgeof the function and structure of the endothelin peptide family shouldprovide insight in the progression and treatment of such conditions.

To aid in gaining further understanding of and to develop treatments forendothelin-mediated or related disorders, there is a need to identifycompounds that modulate or alter endothelin activity. Identification ofcompounds that modulate endothelin activity, such as those that act asspecific antagonists or agonists, may not only aid in elucidating thefunction of endothelin, but may yield in therapeutically usefulcompounds. In particular, compounds that specifically interfere with theinteraction of endothelin peptides with the ET_(A) or ET_(B) receptorsshould be useful in identifying essential characteristics of endothelinpeptides, should aid in the design of therapeutic agents, and may beuseful as disease specific therapeutic agents.

Therefore, it is an object herein to provide compounds that have theability to modulate the biological activity of one or more of theendothelin isopeptides. It is another object to provide compounds thathave use as specific endothelin antagonists. It is also an object to usecompounds that specifically interact with or inhibit the interaction ofendothelin peptides with ET_(A) or ET_(B) receptors. Such compoundsshould be useful as therapeutic agents for the treatment ofendothelin-mediated diseases and disorders and also for theidentification of endothelin receptor subtypes.

SUMMARY OF THE INVENTION

Sulfonamides and methods for modulating the interaction of an endothelinpeptide with ET_(A) and/or ET_(B) receptors are provided. In particular,sulfonamides and methods for inhibiting the binding of an endothelinpeptide to ET_(A) or ET_(B) receptors are provided. The methods areeffected by contacting the receptors with one or more the sulfonamidesprior to, simultaneously with, or subsequent to contacting the receptorswith an endothelin peptide. The sulfonamides are substituted orunsubstituted monocyclic or polycyclic aromatic or heteroaromaticsulfonamides, such as benzene sulfonamides, naphthalene sulfonamides andthiophene sulfonamides. Particularly preferred sulfonamides areN-isoxazolyl sulfonamides. More particularly preferred among suchsulfonamides are those in which Ar² is a heterocycle that contains onering, multiple rings or fused rings, typically two or three rings andone or two heteroatoms in the ring or rings.

The sulfonamides have formula I:

in which Ar¹ is a substituted or unsubstituted aryl group with one ormore substituents, including an alkyl group, an aryl group, asubstituted aryl group, a nitro group, an amino group or a halide or isan alkyl group. In particular, Ar¹ is alkyl or is a five or six memberedsubstituted or unsubstituted aromatic or heteroaromatic ring,particularly 3- or 5-isoxazolyl and pyridazinyl, and also includingthiazolyl, including 2-thiazolyl, pyrimidinyl, including 2-pyrimidinyl,or substituted benzene groups, including aryloxy substituted benzenegroups or is a bicyclic or tricyclic carbon or heterocyclic ring.

Ar¹ is, in certain embodiments, selected from groups such as:

and the substituents represented by R are selected from, for example, H,NH₂, halide, pseudohalide, alkyl, alkylcarbonyl, formyl, an aromatic orheteroaromatic group, alkoxyalkyl, alkylamino, alkylthio, arylcarbonyl,aryloxy, arylamino, arylthio, haloalkyl, haloaryl, carbonyl, in whichthe aryl and alkyl portions, are unsubstituted or substituted with anyof the preceding groups, and straight or branched chains of from about 1up to about 10-12 carbons, preferably, 1 to about 5 or 6 carbons. R ispreferably H, NH₂, halide, CH₃, CH₃O or another aromatic group. Ar² isany group such that the resulting sulfonamide inhibits binding by 50%,compared to binding in the absence of the sulfonamide, of an endothelinpeptide to an endothelin receptor at a concentration of less than about100 μM, except that Ar² is not phenyl or naphthyl when Ar¹ isN-(5-isoxazolyl) or N-(3-isoxazolyl) unless the isoxazole is a4-halo-isoxazole, a 4-higher alkyl (C₈ to C₁₅)-isoxazole, or thecompound is a 4-biphenyl that is unsubstituted at the 2 or 6 position onthe sulfonamide-linked phenyl group.

In the embodiments described in detail herein, Ar¹ is an isoxazole andcompounds are represented by the formulae II:

in which R¹ and R² are either (i), (ii) or (iii) as follows:

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, alkyloxy, haloalkyl, alkylsufinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl,haloalkyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl,arylcarbonyl, formyl, substituted or unsubstituted amido, substituted orunsubstituted ureido, in which the alkyl, alkenyl and alkynyl portionscontain from 1 up to about 14 carbon atoms and are either straight orbranched chains or cyclic, and the aryl portions contain from about 4 toabout 16 carbons, except that R² is not halide or pseudohalide; or,

(ii) R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or,

(iii) R¹ and R² together form 1,3-butadienyl, and with the above provisothat Ar² is not phenyl or naphthyl when Ar¹ is N-(5-isoxazolyl) orN-(3-isoxazolyl) unless the isoxazole is a 4-halo-isoxazole, a 4-higheralkyl (C₈ to C₁₅)-isoxazole, or the compound is a 4-biphenylsulfonamidethat is unsubstituted at the 2 or 6 position on the sulfonamide-linkedphenyl group.

In preferred embodiments herein, R¹ and R² are each selectedindependently from among alkyl, lower alkenyl, lower alkynyl, lowerhaloalkyl, halide, pseudohalide or H, except that R² is not halide;

Ar² is any group such that the resulting sulfonamide inhibits binding by50%, compared to binding in the absence of the sulfonamide, of anendothelin peptide to an endothelin receptor at a concentration of lessthan about 100 μM, with the above proviso. In particular, Ar² is asubstituted or unsubstituted group selected from among groups including,but not limited to, the following: naphthyl, phenyl, biphenyl, quinolyl,styryl, thienyl, furyl, isoquinolyl, pyrrolyl, benzofuranyl, pyridinyl,thionaphthalyl, indolyl, alkyl, and alkenyl. It is understood that thepositions indicated for substituents, including the sulfonamide groups,may be varied. Thus, for example, compounds herein encompass groups thatinclude thiophene-3-sulfonamides and thiophene-2-sulfonamides.

In certain embodiments described in detail herein, Ar² is a single ringheterocycle, particularly a 5-membered ring, or is a fused bicyclic ortricyclic heterocycle that contains one or more, particularly one,heteroatom selected from S, O and NR⁴², in the ring, where R⁴² containsup to about 30 carbon atoms, preferably 1 to 10, more preferably 1 to 6and is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R¹⁵ and S(O)_(n)R¹⁵ in which n is 0-2; R¹⁵ is hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl; R⁴² and R¹⁵ are unsubstituted orare substituted with one or more substituents each selectedindependently from Z, which as defined herein, includes hydrogen,halide, pseudoahlide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aminoacids, primary and secondary, O-glycosides, amides, hexoses, riboses,alkylaryl, alkylheteroaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ inwhich n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶ and CONR¹²R¹⁶;R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl, a sulfonylchloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, —C(O)NHR⁵⁰,—(CH₂)_(x)OH; R¹², which is selected independently from R⁴² and Z, isselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R¹⁷ and S(O)_(n)R¹⁷ in which n is 0-2; and R¹⁷ is hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl or cycloalkynyl; each of R⁴², R¹², R¹⁵ and R¹⁶may be further substituted with the any of the appropriate groups ofthose set forth for Z.

In preferred embodiments herein, R⁴² is aryl, such as phenyl or alkylphenyl, hydrogen or loweralkyl.

Thus, in the compounds provided herein Ar² includes thienyl, furyl andpyrrolyl, benzofuryl, benzopyrolyl, benzothienyl, benzo[b]furyl,benzo[b]thienyl, and indolyl (benzo[b]pyrrolyl) and 4-biphenyl, and Ar¹is preferably N-(5-isoxazolyl) or N-(3-isoxazolyl).

These sulfonamides include N-isoxazolyl sulfonamides that have formulaIII:

in which X is S, O or NR¹¹ in which R¹¹ contains up to about 30 carbonatoms, preferably 1 to 10, more preferably 1 to 6 and is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl , cycloalkenyl , cycloalkynyl, C(O) R¹⁵and S(O)_(n)R¹⁵ in which n is 0-2; R¹⁵ is hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl; R¹¹ and R¹⁵ are unsubstituted or aresubstituted with one or more substituents each selected independentlyfrom Z, which is selected from substituents that include, but are notlimited to, hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl,alkynyl, aryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ inwhich n is 0-2, a D, L or racemic amino acid, a ribose or hexose, anO-glycoside, a sulfonyl chloride, alkylaryl, heterocyclyl, a sulfonylchloride, a primary or secondary amide, S(O)₂NHR⁵⁰, alkylaryl,alkylheteroaryl, —C(O)NHR⁵⁰, —(CH₂)_(x)OH, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶,R¹²NCOR¹⁶ and CONR¹²R¹⁶; R⁵⁰ is a substituent such as hydrogen, loweralkyl, lower alkoxy; R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; R¹², which is selected independently from R¹¹ and Z, isselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R¹⁷ and S(O)_(n)NR¹⁷ in which n is 0-2; and R¹⁷ is hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl or cycloalkynyl; each of R¹¹, R¹², R¹⁵ and R¹⁶may be further substituted with the any of the groups set forth for Z,and R¹¹ is preferably hydrogen, aryl, such as phenyl or alkyl phenyl,loweralkyl.

Among the embodiments described in detail herein, Ar² is thienyl, furyl,pyrrolyl or a group that is a derivative or analog, as described below,of a thienyl, furyl or pyrrolyl group, including benzo[b] derivativessuch as a benzo[b]thienyl, Ar¹ is N-(5-isoxazolyl) or N-(3-isoxazolyl).

In particular, Ar² has the formula IV:

in which X is O, S or NR¹¹, where R¹¹ is as defined above; that can besubstituted at any or all positions or is an analog or derivative of thegroups of formula (IV) in which the substituents form fused aromatic,aliphatic or heterocyclic rings; and R⁸, R⁹ and R¹⁰ are eachindependently selected as follows from (i) or (ii):

(i) R⁸, R⁹ and R¹⁰, which each contain hydrogen or up to about 50 carbonatoms, generally up to about 30, more generally 20 or fewer, are eachindependently selected from hydrogen, halide, pseudohalide, alkyl,alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸,acetoxy-(CH═CH)—, CO₂R¹⁸, SH, (CH₂)_(r)C(O)(CH₂)_(n)R¹⁸,—(CH₂)_(x)C(O)—W-aryl or —(CH₂)_(x)C(O)—W-heteroaryl,(CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O) (CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸, S(O)_(m)R¹⁸ in which:

aryl is a single or two or three fused rings that contains 5 to 7members in the ring, and is preferably substituted, with substituentssuch as those set forth for Z, at two or more positions;

heteroaryl a single or two or three fused rings that contains 5 to 7members in each ring, and one to two heteroatoms, and is preferablysubstituted, with substituents such as those set forth for Z, at two ormore positions;

W includes ═C(halo)₂, ═N(H), ═(CH₂)_(x)COOH where x is 0 to 6, ═N(loweralkyl), ═C(O), lower alkyl, alkyl which is straight or branchedcontaining 1 to 6 carbons, ═C(lower alkyl)₂,

x is 0 to 6, preferably 0 to 3, more preferably 0-2;

m is 0-2, s, n and r are each independently 0 to 6, preferably 0-3,HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸, in which R¹⁹ isselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R²⁰, S(O)_(n)R²⁰ in which n is 0-2; andR¹⁸ and R²⁰ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; and

any of the groups set forth for R⁸, R⁹ and R¹⁰ are unsubstituted orsubstituted with any substituents set forth for Z, which as set forthabove, includes hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl,alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_(n)R²¹ inwhich n is 0-2, an amino acid, a ribose or hexose, a sulfonyl chloride,an O-glycoside, alkylaryl, heterocyclyl, a sulfonyl chloride, a primaryor secondary amide, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, —C(O)NHR⁵⁰,—(CH₂)_(x)OH, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ and CONR²²R²¹; R²²is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, C(O)R²³ and S(O)_(n)R²³ in which n is 0-2; R⁵⁰ ishydrogen, lower alkyl, lower alkoxy; and R²¹ and R²³ are independentlyselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl,

with the proviso that if R⁸ is NR¹⁸R¹⁹, OR¹⁸ R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸CO₂R¹⁸, (CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸ or (CH₂)_(r)R¹⁸ andR¹⁸ is an aryl group containing 5 or 6 members, then the aryl group hasat least two substituents, and preferably one substituent at the2-position relative to the linkage to the thienyl, furyl or pyrrolyl,and preferably has more than, two substituents; or

(ii) any two of R⁸, R⁹ and R¹⁰ with the carbon to which each is attachedform an aryl, aromatic ring, heteroaromatic ring, carbocyclic orheterocyclic ring, which is saturated or unsaturated, containing fromabout 3 to about 16 members, preferably 3 to about 10 members, morepreferably 5 to 7 members that is substituted with one or moresubstituents, each substituent is independently selected from Z; theother of R⁸, R⁹ and R¹⁰ is selected as in (i); and the heteroatoms areNR¹¹, O, or S, with the proviso that Ar² is not5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl,5-halo-3-loweralkylbenzo[b]pyrrolyl.

In the embodiments provided herein, the alkyl, alkynyl and alkenylportions of each listed substituent are straight or branched chains,acyclic or cyclic, and preferably have from about 1 up to about 10carbons; in more preferred embodiments they have from 1-6 carbons. Thearyl, alicyclic, aromatic rings and heterocyclic groups can have from 3to 16, generally, 3-7, more often 5-7 members in the rings, and may besingle or fused rings. The ring size and carbon chain length areselected up to an amount that the resulting molecule binds and retainsactivity as an endothelin antagonist or agonist, such that the resultingcompound inhibits binding by 50%, compared to binding in the absence ofthe sulfonamide, of an endothelin peptide to an endothelin receptor at aconcentration of less than about 100 μM.

In preferred embodiments of interest herein, R⁹ and R¹⁰ are hydrogen,halide or methyl, more preferably hydrogen or halide, and R⁸ is selectedfrom CO₂R¹⁸, (CH₂)_(r)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸, —(CH₂)_(x)C(O)—W-aryl or—(CH₂)_(x)C(O)—W-heteroaryl, (CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸, with the proviso that if R⁸ isCO₂R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸ or (CH₂)_(r)R¹⁸ and R¹⁸ is phenyl, thephenyl group is substituted at least two positions, and preferably, atleast one of those positions is ortho.

In the preferred compounds, the aryl groups and heteroaryl groupspreferably contain 5 to 7 members in the ring and R¹⁸ is aryl orheteroaryl, preferably having 5 or 6 members in the ring, morepreferably phenyl or pyrimidinyl, most preferably phenyl.

In the most preferred compounds herein, R¹⁸ is phenyl, which issubstituted at more than one position, and most preferably at least onesubstituent is at the ortho position, and more preferably is substitutedat the 2, 3, 4 and 6 positions, R⁹ and R¹⁰ are each hydrogen, halide orloweralkyl, preferably hydrogen, and R⁸ is C(O)NHR¹⁸, C(O)CH₂R¹⁸,(CH₂)R¹⁸, —(CH₂)_(x)C(O)—W-R¹⁸ or —(CH₂)_(x)C(O)—W-R¹⁸, where R¹⁸ ispreferably Z-substituted phenyl, with the proviso that if R⁸ isC(O)NHR¹⁸ and R¹⁸ is phenyl, then the phenyl group must have at leasttwo substituents, preferably one of the substituents is in the orthoposition. More preferably, if R¹⁸ is phenyl, then the phenyl issubstituted at three or more, preferably at the 2, 3, 4 and 6,positions.

In other preferred embodiments, Ar² is a benzo[b]thienyl, benzo[b]furyl,or indolyl (benzo[b]pyrrolyl), with the proviso that the benzene ring issubstituted and the substituents are other than 5 halo, 3-loweralkyl.Preferred substituents on the benzene ring, include, but are not limitedto, one or more selected from alkylenedioxy, particularlymethylenedioxy, preferably 3,4-methylenedioxy, ethylenedioxy, aryl,particularly phenyl, dimethylamino, diethylamino, benzyl, alkoxy,particularly lower alkoxy, such as methoxy and ethoxy, halide, andalkyl, preferably loweralkyl.

In the preferred compounds herein, R² is preferably, selected from amongalkyl, lower alkenyl, lower alkynyl, lower haloalkyl or H; and R¹ ishalide or loweralkyl, and more preferably, R¹ is bromide or chloride,methyl or ethyl. In the most active compounds provided herein, asevidenced by in vitro binding assays, R¹ is bromide or chloride. For usein vivo R¹ is preferably chloride.

Of the compounds described herein, those that inhibit or increase anendothelin-mediated activity by about 50% at concentrations of less,than about 10 μM are preferred. More preferred are those that inhibit orincrease an endothelin-mediated activity by about 50% at concentrationsof less than about 1 μM, more preferably less than about 0.1 μM, evenmore preferably less than about 0.01 μM, and most preferably less thanabout 0.001 μM. It is noted that, as described below, the IC₅₀concentration determined in the in vitro assays is a non-linear functionof incubation temperature. The preferred values recited herein refer tothe assays that are performed at 4° C. When the assays are performed at24° C., somewhat higher (see, Table 1) IC₅₀ concentrations are observed.Accordingly, the preferred IC₅₀ concentrations are about 10-fold higher.

Also among the most preferred compounds for use in methods providedherein, are those that are ET_(A) selective, i.e., they interact withET_(A) receptors at substantially lower concentrations (at an IC₅₀ atleast about 10-fold lower, preferably 100-fold lower) than they interactwith ET_(B) receptors. In particular, compounds that interact withET_(A) with an IC₅₀ of less than about 10 μM, preferably less than 1 μM,more preferably less than 0.1 μM, but with ET_(B) with an IC₅₀ ofgreater than about 10 μM or compounds that interact with ET_(B) with anIC₅₀ of less than about 10 μM, preferably less than 1 μM, morepreferably less than 0.1 μM, but with ET_(A) with an IC₅₀ of greaterthan about 10 μM are preferred.

Preferred compounds also include compounds that are ET_(B) receptorselective or that bind to ET_(B) receptors with an IC₅₀ of less thanabout 1 μM. ET_(B) selective compounds interact with ET_(B) receptors atIC₅₀ concentrations that are at least about 10-fold lower than theconcentrations at which they interact with ET_(A) receptors. In thesecompounds, R² is selected from among alkyl, lower alkenyl, loweralkynyl, lower haloalkyl, halide or H; and R¹ is halide or loweralkyl,and in preferred embodiments, R¹ is bromide or chloride, preferablychloride; R⁹ and R¹⁰ are selected independently from hydrogen,loweralkyl, preferably methyl or ethyl, or halide, and R⁸, which is thesubstituent at the 5-position (see, e.g., formulae III and IV), isC(O)—W-aryl C(O)—W-heteroaryl in which W is as defined below, aryl or aheterocycle, particularly phenyl and isoxazolyl, which are unsubstitutedor substituted with Z, which is preferably loweralkyl or halide or, whensubstituted on the 2-position of the phenyl group also is, among otherselections, C(O)R²¹, CO₂R²¹, S(O)_(n)R²¹ in which n is 0-2, an aminoacid, a ribose or hexose, a sulfonyl chloride, alkylaryl, heterocyclyl,a sulfonyl chloride, a primary or secondary amide, S(O)₂NHR⁵⁰,alkylaryl, alkylheteroaryl, —C(O)NHR⁵⁰, —(CH₂)_(x)OH, NHOH, NR²²R²¹,NO₂, N₃, OR²¹, R²²NCOR²¹ and CONR²²R²¹; R²² is selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, alkoxy,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R²³ andS(O)_(n)R²³ in which n is 0-2; R⁵⁰ is hydrogen, lower alkyl, loweralkoxy; and R²¹ and R²³ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl or cycloalkynyl.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein or pharmaceutically acceptablesalts or acids thereof that deliver amounts effective for the treatmentof hypertension, stroke, asthma, shock, ocular hypertension, glaucoma,renal failure, inadequate retinal perfusion and other conditions thatare in some manner mediated by an endothelin peptide or that involvevasoconstriction or whose symptoms can be ameliorated by administrationof an endothelin antagonist or agonist, are also provided. Particularlypreferred compositions are those that deliver amounts effective for thetreatment of hypertension or renal failure. The effective amounts andconcentrations are effective for ameliorating any of the symptoms of anyof the disorders.

Methods for inhibiting binding of an endothelin peptide to an endothelinreceptor are provided. These methods are practiced by contacting thereceptor with one or more of the compounds provided hereinsimultaneously, prior to, or subsequent to contacting the receptor withan endothelin peptide.

Methods for treatment of endothelin-mediated disorders, including butnot limited to, hypertension, asthma, shock, ocular hypertension,glaucoma, inadequate retinal perfusion and other conditions that are insome manner mediated by an endothelin peptide, or for treatment ofdisorder that involve vasoconstriction or that are ameliorated byadministration of an endothelin antagonist or agonist are provided.

In particular, methods of treating endothelin-mediated disorders byadministering effective amounts of the sulfonamides, prodrugs or othersuitable derivatives of the sulfonamides are provided. In particular,methods for treating endothelin-mediated disorders, includinghypertension, cardiovascular diseases, cardiac diseases includingmyocardial infarction, pulmonary hypertension, erythropoietin-mediatedhypertension, respiratory diseases and inflammatory diseases, includingasthma, bronchoconstriction, ophthalmologic diseases, gastroentericdiseases, renal failure, endotoxin shock, menstrual disorders, obstetricconditions, wounds, anaphylactic shock, hemorrhagic shock, and otherdiseases in which endothelin mediated physiological responses areimplicated, by administering effective amounts of one or more of thecompounds provided herein in pharmaceutically acceptable carriers areprovided. Preferred methods of treatment are methods for treatment ofhypertension and renal failure.

More preferred methods of treatment are those in which the compositionscontain at least one compound that inhibits the interaction ofendothelin-1 with ET_(A) receptors at an IC₅₀ of less than about 10 μM,and preferably less than about 5 μM, more preferably less than about 1μM, even more preferably less than 0.1 μM, and most preferably less than0.05 μM. Other preferred methods are those in which the compositionscontain one or more compounds that is (are) ET_(A) selective or one ormore compounds that is (are) ET_(B) selective. Methods in which thecompounds are ET_(A) selective are for treatment of disorders, such ashypertension; and methods in which the compounds are ET_(B) selectiveare for treatment of disorders, such as asthma, that requirebronchodilation.

In practicing the methods, effective amounts of compositions containingtherapeutically effective concentrations of the compounds formulated fororal, intravenous, local and topical application for the treatment ofhypertension, cardiovascular diseases, cardiac diseases, includingmyocardial infarction, respiratory diseases, including asthma,inflammatory diseases, ophthalmologic diseases, gastroenteric diseases,renal failure, immunosuppressant-mediated renal vasoconstriction,erythropoietin-mediated vasoconstriction, endotoxin shock, anaphylacticshock, hemorrhagic shock, pulmonary hypertension, and other diseases inwhich endothelin mediated physiological responses are implicated areadministered to an individual exhibiting the symptoms of one or more ofthese disorders. The amounts are effective to ameliorate or eliminateone or more symptoms of the disorders.

Methods for the identification and isolation of endothelin receptorsubtypes are also provided. In particular, methods for detecting,distinguishing and isolating endothelin receptors using the disclosedcompounds are provided. In particular, methods are provided fordetecting, distinguishing and isolating endothelin receptors using thecompounds provided herein.

In addition, methods for identifying compounds that are suitable For usein treating particular diseases based on their preferential affinity fora particular endothelin receptor subtype are also provided.

Articles of manufacture containing packaging material, a compoundprovided herein, which is effective for ameliorating the symptoms of anendothelin-mediated disorder, antagonizing the effects of endothelin orinhibiting binding of an endothelin peptide to an ET receptor with anIC₅₀ of less than about 10 μM, within the packaging material, and alabel that indicates that the compound or salt thereof is used forantagonizing the effects of endothelin, treating an endothelin-mediateddisorder, or inhibiting the binding of an endothelin peptide to an ETreceptor are provided.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. All patents and publicationsreferred to herein are incorporated by reference.

As used herein, endothelin (ET) peptides include peptides that havesubstantially the amino acid sequence of endothelin-1, endothelin-2 orendothelin-3 and that act as potent endogenous vasoconstrictor peptides.

As used herein, an endothelin-mediated condition is a condition that iscaused by abnormal endothelin activity or one in which compounds thatinhibit endothelin activity have therapeutic use. Such diseases include,but are not limited to hypertension, cardiovascular disease, asthma,inflammatory diseases, ophthalmologic disease, menstrual disorders,obstetric conditions, gastroenteric disease, renal failure, pulmonaryhypertension, endotoxin shock, anaphylactic shock, or hemorrhagic shock.Endothelin-mediated conditions also include conditions that result fromtherapy with agents, such as erythropoietin and immunosuppressants, thatelevate endothelin levels.

As used herein an effective amount of a compound for treating aparticular disease is an amount that is sufficient to ameliorate, or insome manner reduce the symptoms associated with the disease. Such amountmay be administered as a single dosage or may be administered accordingto a regimen, whereby it is effective. The amount may cure the diseasebut, typically, is administered in order to ameliorate the symptoms ofthe disease. Typically, repeated administration is required to achievethe desired amelioration of symptoms.

As used herein, an endothelin agonist is a compound that potentiates orexhibits a biological activity associated with or possessed by anendothelin peptide.

As used herein, an endothelin antagonist is a compound, such as a drugor an antibody, that inhibits endothelin-stimulated vasoconstriction andcontraction and other endothelin-mediated physiological responses. Theantagonist may act by interfering with the interaction of the endothelinwith an endothelin-specific receptor or by interfering with thephysiological response to or bioactivity of an endothelin isopeptide,such as vasoconstriction. Thus, as used herein, an endothelin antagonistinterferes with endothelin-stimulated vasoconstriction or other responseor interferes with the interaction of an endothelin with anendothelin-specific receptor, such as ET_(A) receptors, as assessed byassays known to those of skill in the art.

The effectiveness of potential agonists and antagonists can be assessedusing methods known to those of skill in the art. For example,endothelin agonist activity can be identified by its ability tostimulate vasoconstriction of isolated rat thoracic aorta or portal veinring segments (Borges et al. (1989) “Tissue selectivity of endothelin”Eur. J. Pharmacol. 165: 223-230). Endothelin antagonist activity can beassessed by the ability to interfere with endothelin-inducedvasoconstriction. Exemplary assays are set forth in the EXAMPLES. Asnoted above, the preferred IC₅₀ concentration ranges are set forth withreference to assays in which the test compound is incubated with the ETreceptor-bearing cells at 4° C. Data presented for assays in which theincubation step is performed at the less preferred 24° C. areidentified. It is understood that for purposes of comparison, theseconcentrations are somewhat higher than the concentrations determined at4° C.

As used herein, the biological activity or bioactivity of endothelinincludes any activity induced, potentiated or influenced by endothelinin vivo. It also includes the ability to bind to particular receptorsand to induce a functional response, such as vasoconstriction. It may beassessed by in vivo assays or by in vitro assays, such as thoseexemplified herein. The relevant activities include, but are not limitedto, vasoconstriction, vasorelaxation and bronchodilation. For example,ET_(B) receptors appear to be expressed in vascular endothelial cellsand may mediate vasodilation and other such responses; whereas ET_(A)receptors, which are endothelin-1-specific, occur on smooth muscle andare linked to vasoconstriction Any assay known to those of skill in theart to measure or detect such activity may be used to assess suchactivity (see, e.g., Spokes et al. (1989) J. Cardiovasc. Pharmacol.13(Suppl. 5):S191-S192; Spinella et al. (1991) Proc. Natl. Acad. Sci.USA 88: 7443-7446; Cardell et al. (1991) Neurochem. Int. 18:571-574);and the Examples herein).

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as binding of endothelin to tissue receptors, in an assaythat measures such response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

As used herein a sulfonamide that is ET_(A) selective refers tosulfonamides that exhibit an IC₅₀ that is at least about 10-fold lowerwith respect to ET_(A) receptors than ET_(B) receptors.

As used herein, a sulfonamide that is ET_(B) selective refers tosulfonamides that exhibit an IC₅₀ that is at least about 10-fold lowerwith respect to ET_(B) receptors than ET_(A) receptors.

As used herein, pharmaceutically acceptable salts, esters or otherderivatives of the compounds include any salts, esters or derivativesthat may be readily prepared by those of skill in this art using knownmethods for such derivatization and that produce compounds that may beadministered to animals or humans without substantial toxic effects andthat either are pharmaceutically active or are prodrugs. For example,hydroxy groups can be esterified or etherified.

As used herein, treatment means any manner in which the symptoms of aconditions, disorder or disease are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use as contraceptive agents.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular pharmaceutical composition refers to anylessening, whether permanent or temporary, lasting or transient that canbe attributed to or associated with administration of the composition.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis and high performance liquid chromatography (HPLC), usedby those of skill in the art to assess such purity, or sufficiently puresuch that further purification would not detectably alter the physicaland chemical properties, such as enzymatic and biological activities, ofthe substance. Methods for purification of the compounds to producesubstantially chemically pure compounds are known to those of skill inthe art. A substantially chemically pure compound may, however, be amixture of stereoisomers. In such instances, further purification mightincrease the specific activity of the compound.

As used herein, biological activity refers to the in vivo activities ofa compound or physiological responses that result upon in vivoadministration of a compound, composition or other mixture. Biologicalactivity, thus, encompasses therapeutic effects and pharmaceuticalactivity of such compounds, compositions and mixtures.

As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized or otherwise converted to thebiologically, pharmaceutically or therapeutically active form of thecompound. To produce a prodrug, the pharmaceutically active compound ismodified such that the active compound will be regenerated by metabolicprocesses The prodrug may be designed to alter the metabolic stabilityor the transport characteristics of a drug, to mask side effects ortoxicity, to improve the flavor of a drug or to alter othercharacteristics or properties of a drug. By virtue of knowledge ofpharmacodynamic processes and drug metabolism in vivo, those of skill inthis art, once a pharmaceutically active compound is known, can designprodrugs of the compound (see, e.g., Nogrady (1985) Medicinal ChemistryA Biochemical Approach, Oxford University Press, New York, pages388-392). For example, succinyl-sulfathiazole is a prodrug of4-amino-N-(2-thiazoyl)benzenesulfonamide (sulfathiazole) that exhibitsaltered transport characteristics.

As used herein, acid isostere means a group that is significantlyionized at physiological pH. Examples of suitable acid isosteres includesulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl,arylsulfonylcarbamoyl or heteroarylsulfonylcarbamoyl.

As used herein, halo or halide refers to the halogen atoms; F, Cl, Brand I.

As used herein, pseudohalides are compounds that behave substantiallysimilar to halides. Such compounds can be used in the same manner andtreated in the same manner as halides (X⁻, in which X is a halogen, suchas Cl or Br). Pseudohalides include, but are not limited to cyanide,cyanate, thiocyanate, selenocyanate and azide.

As used herein, haloalkyl refers to a loweralkyl radical in which one ormore of the hydrogen atoms are replaced by halogen including, but notlimited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl andthe like.

As used herein, alkyl means an aliphatic hydrocarbon group that is astraight or branched chain preferably having about 1 to 12 carbon atomsin the chain. Preferred alkyl groups are loweralkyl groups which arealkyls containing 1 to about 6 carbon atoms in the chain. Branched meansthat one or more loweralkyl groups such as methyl, ethyl or propyl areattached to a linear alkyl chain. The alkyl group may be unsubstitutedor independently substituted by one or more groups, such as, but notlimited to: halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino andimino. Exemplary alkyl groups include methyl, ethyl, propyl, methanoicacid, ethanoic acid, propanoic acid, ethanesulfinic acid and ethanesulfonic acid.

As used herein the term lower describes alkyl, alkenyl and alkynylgroups containing about 6 carbon atoms or fewer. It is also used todescribe aryl groups or heteroaryl groups that contain 6 or fewer atomsin the ring. Loweralkyl, lower alkenyl, and lower alkynyl refer tocarbon chains having less than about 6 carbons. In preferred embodimentsof the compounds provided herein that include alkyl, alkenyl, or alkynylportions include loweralkyl, lower alkenyl, and lower alkynyl portions.

As used herein, alkenyl means an aliphatic hydrocarbon group containinga carbon-carbon double bond and which may be straight or branchedchained having from about 2 to about 10 carbon atoms in the chain.Preferred alkenyl groups have 2 to about 4 carbon atoms in the chain.Branched means that one or more loweralkyl or lower alkenyl groups areattached to a linear alkenyl chain. The alkenyl group may beunsubstituted or independently substituted by one or more groups, suchas halo, carboxy, formyl, sulfo, sulfino, carbamoyl, amino and imino.Exemplary alkenyl groups include ethenyl, propenyl, carboxyethenyl,carboxypropenyl, sulfinoethenyl and sulfonoethenyl.

As used herein, alkynyl means an aliphatic hydrocarbon group containinga carbon-carbon triple bond and which may be straight or branched havingabout 2 to 10 carbon atoms in the chain. Branched means that one or moreloweralkyl, alkenyl or alkynyl groups are attached to a linear alkynylchain. An exemplary alkynyl group is ethynyl.

As used herein, aryl means an aromatic monocyclic or multicyclichydrocarbon ring system containing from 3 to 15 or 16 carbon atoms,preferably from 5 to 10. Aryl groups include, but are not limited togroups, such as phenyl, substituted phenyl, napthyl, substitutednaphthyl, in which the substituent is loweralkyl, halogen, or loweralkoxy. Preferred aryl groups are lower aryl groups that contain lessthan 7 carbons in the ring structure.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. are usedas is generally understood by those of skill in this art. For example,as used herein alkyl refers to saturated carbon chains that contain oneor more carbons; the chains may be straight or branched or includecyclic portions or be cyclic. As used herein, alicyclic refers to arylgroups that are cyclic.

As used herein, cycloalkyl refers to saturated cyclic carbon chains;cycloalkyenyl and cycloalkynyl refer to cyclic carbon chains thatinclude at least one unsaturated double or triple bond, respectively.The cyclic portions of the carbon chains may include one ring or two ormore fused rings.

As used herein, cycloalkenyl means a non-aromatic monocyclic ormulticyclic ring system containing a carbon-carbon double bond andhaving about 3 to about 10 carbon atoms. Exemplary monocycliccycloalkenyl rings include cyclopentenyl or cyclohexenyl; preferred iscyclohexenyl. An exemplary multicyclic cycloalkenyl ring isnorbornylenyl. The cycloalkenyl group may be independently substitutedby one or more halo or alkyl.

As used herein, “haloalkyl” refers to a loweralkyl radical in which oneor more of the hydrogen atoms are replaced by halogen including, but notlimited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl andthe like.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “carboxamide” refers to groups of formula R_(p)CONH₂ inwhich R is selected from alkyl or aryl, preferably loweralkyl or loweraryl and p is 0 or 1.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R ishydrogen, alkyl, preferably loweralkyl or aryl, preferably lower aryl.

As used herein “dialkylaminocarbonyl” as used herein refers to —C(O)NR′Rin which R¹ and R are independently selected from alkyl or aryl,preferably loweralkyl or loweraryl; “carboxamide” refers to groups offormula NR′COR.

As used herein, “alkoxycarbonyl” as used herein refers to —C(O)OR inwhich R is alkyl, preferably loweralkyl or aryl, preferably lower aryl.

As used herein, “alkoxy” and “thioalkoxy” refer to RO— and RS—, in whichR is alkyl, preferably loweralkyl or aryl, preferably lower aryl.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R isalkyl, preferably loweralkyl or aryl, preferably lower aryl.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl,preferably loweralkyl.

As used herein, cycloalkyl refers to satured cyclic carbon chains;cycloalkyenyl and cycloalkynyl refer to cyclic carbon chains thatinclude at least one unsaturated triple bond. The cyclic portions of thecarbon chains may include one ring or two or more fused rings.

As used herein, alkylenedioxy means an —O-alkyl-O— group in which thealkyl group is as previously described. A replacement analog ofalkylenedioxy means an alkylenedioxy in which one or both of the oxygenatoms is replaced by a similar behaving atom or group of atoms such as,S, N, NH, Se. An exemplary replacement alkylenedioxy group isethylenebis(sulfandiyl). Alkylenethioxyoxy is —S-alkyl-O—, —O-alkyl-S—and alkylenedithioxy is —S-alkyl-S—.

As used herein, heteroaryl means an aromatic monocyclic or fused ringsystem in which one or more of the carbon atoms in the ring systemis(are) replaced by an element(s) other than carbon, for examplenitrogen, oxygen or sulfur. Preferred cyclic groups contain one or twofused rings and include from about 3 to about 7 members in each ring.Similar to “aryl groups”, the heteroaryl groups may be unsubstituted orsubstituted by one or more substituents. Exemplary heteroaryl groupsinclude pyrazinyl, pyrazolyl, tetrazolyl, furanyl, (2- or 3-)thienyl,(2-,3- or 4-)pyridyl, imidazoyl, pyrimidinyl, isoxazolyl, thiazolyl,isothiazolyl, quinolinyl, indolyl, isoquinolinyl, oxazolyl and1,2,4-oxadiazolyl. Preferred heteroaryl groups include 5 to 6-memberednitrogen-containing rings, such as pyrimidinyl.

As used herein, alkoxycarbonyl means an alkyl-O—CO— group. Exemplaryalkoxycarbonyl groups include methoxy- and ethoxycarbonyl.

As used herein, carbamoyl means —CONH₂. As with all groups describedherein, these groups may be unsubstituted or substituted. Substitutedcarbamoyl includes groups such as —CONY²Y³ in which Y² and Y³ areindependently hydrogen, alkyl, cyano(loweralkyl), aryalkyl,heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substitutedloweralkyl), carboxy(carboxy substituted loweralkyl), carboxy(hydroxysubstituted loweralkyl), carboxy(heteroaryl substituted loweralkyl),carbamoyl(loweralkyl), alkoxycarbonyl(loweralkyl) or alkoxycarbonyl(arylsubstituted loweralkyl), provided that only one of Y² and Y³ may behydrogen and when one of Y² and Y³ is carboxy(loweralkyl), carboxy(arylsubstituted loweralkyl), carbamoyl(loweralkyl),alkoxycarbonyl(loweralkyl) or alkoxycarbonyl(aryl substitutedloweralkyl) then the other of Y² and Y³ is hydrogen or alkyl. Preferredfor Y² and Y³ are independently hydrogen, alkyl, cyano(loweralkyl),aralkyl, heteroaralkyl, carboxy(loweralkyl), carboxy(aryl substitutedloweralkyl) and carbamoyl(loweralkyl).

As used herein, any corresponding N-(4-halo-3-methyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl),N-(4,5-dimethyl-3-isoxazolyl) derivative thereof refers to compounds inwhich Ar² is the same as the compound specifically set forth, but Ar¹ isN-(4-halo-3-methyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl),N-(3,4-dimethyl-5-isoxazolyl), N-(4-halo-5-methyl-3-isoxazolyl),N-(4-halo-3-methyl-5-isoxazolyl), or N-(4,5-dimethyl-3-isoxazolyl) inwhich halo is any halide, preferably Cl or Br.

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944).

A. Compounds for use in treating endothelin-mediated diseases

Compounds and methods for treating endothelin-mediated diseaszes usingthe compounds of formulae I and II are provided. In particular, in thecompounds provided herein, Ar² is thienyl, furyl, pyrrolyl or a group,such as benzofuryl, thianaphthyl or indolyl, that is a derivative oranalog, as described below, of a thienyl, furyl or pyrrolyl group, Ar¹is preferably N-(5-isoxazolyl) or N-(3-isoxazolyl).

Ar² is a thiophene, pyrrole, furan, benzo[b]thiophene, indolyl(benzo[b]pyrrole), or benzo[b]furan Among the compounds provided hereinare those represented by the formula V:

in which R¹ and R² are either (i), (ii) or (iii) as follows:

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkcoxy, alkylamino, alkylthio, haloalkoxy, haloalkyl, alkylsufinyl,alkylsulfonyl, aryloxy, arylamino, arylthio, arylsufinyl, arylsulfonyl,aminocarbonyl, arylaminocarbonyl, haloalkyl, haloaryl, alkoxycarbonyl,alkylcarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido,substituted or unsubstituted ureido, in which the alkyl, alkenyl andalkynyl portions are either straight or branched chains that containfrom 1 up to about 10 carbon atoms, and the aryl portions contain fromabout 4 to about 14 carbons, except the R² is not halide, pseudohalideor higher alkyl; or,

(ii) R¹ and R² together form —(CH₂)_(n), where n is 3 to 6; or,

(iii) R¹ and R² together form 1,3-butadienyl; and

X is S, O or NR¹¹ in which R¹¹ contains up to about 30 carbon atoms,preferably 1 to 10, more preferably 1 to 6 and is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, C(O)R¹⁵ andS(O)_(n)R¹⁵ in which n is 0-2; R¹⁵ is hydrogen, alkyl, alkenyl, alkynyl,aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl; R¹¹ and R¹⁵ are unsubstituted or aresubstituted with one or more substituents each selected independentlyfrom Z, which as defined herein, includes substituents, such ashydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl,amino acids, primary and secondary, O-glycosides, amides, hexoses,riboses, alkylaryl, alkylheteroaryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH,S(O)_(n)R¹⁶ in which n is 0-2, NHOH, NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶and CONR¹²R¹⁶; R¹⁶ is hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl, a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl,alkylheteroaryl, —C(O)NHR⁵⁰, —(CH₂)_(x)OH; R¹², which is selectedindependently from R¹¹ and Z, is selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R¹⁶;R¹⁶ is hydrogen, alkyl, alkenyl,alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl or cycloalkynyl; each of R¹¹, R¹², R¹⁵ and R¹⁶ may befurther substituted with the any of the groups set forth for Z, and R¹¹is preferably hydrogen, aryl, such as phenyl or alkyl phenyl,loweralkyl; and

R⁸, R⁹ and R¹⁰, which each contain hydrogen or up to about 50 carbonatoms, generally up to about 30, more generally 20 or fewer, are eachindependently selected as described above, and more preferably from (i)or (ii) as follows:

(i) R⁹ and R¹⁰ are selected from hydrogen, halide, pseudohalide, alkyl,alkoxy, alkenyl, alkynyl, aryl, aryloxy, heterocyclyl, aralkyl,aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸,(OAC)CH═CHR¹⁸, CO₂R¹⁸, SH, (CH₂)_(r)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸,S(O)_(m)R¹⁸ in which m is 0-2, s, n and r are each independently 0 to 6,preferably 0-3, HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸,in which R¹⁹ is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R²⁰, S(O)_(n)R²⁰ in which n is 0-2; andR¹⁸ and R²⁰ are independently selected from hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl;

R⁸ is selected from C(O)R¹⁸, (OAC)CH═CHR¹⁸, CO₂R¹⁸,(CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(x)COOH where x is 0 to 6, (CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, —(CH₂)_(x)C(O)—W-aryl or—(CH₂)_(x)C(O)—W-heteroaryl where aryl is a single or two or three fusedrings that contains 5 to 7 members in the ring, heteroaryl a single ortwo or three fused rings that contains 5 to 7 members in each ring, andone to two heteroatoms and W is —(C(halo)₂-, —N(H)—, —N(lower alkyl)-,—C(O)—, lower alkyl, or alkyl which is straight or branched containing 1to 6 carbons, —C(lower alkyl)₂-, m is 0-2, s, n and r are eachindependently 0 to 6, preferably −3, R¹⁸ is aryl, more preferablyphenyl, most preferably Z-substituted phenyl,

with the proviso that, if R⁸ is (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸,particularly if r is 0 and/or n is 0, and R¹⁸ is aryl, particularlyphenyl, then R¹⁸ must have two or more substituents, with preferably atleast one ortho substituent;

where any of the groups set forth for R⁸, R⁹ and R¹⁰ are unsubstitutedor substituted with any substituents set forth for Z, which as set forthabove, includes hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl,alkynyl, aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)NR²¹ inwhich n is 0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ and CONR²²R²¹;R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, C(O)R²³ and S(O)NR²³ in which n is 0-2; and R²¹ and R²³are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl orcycloalkynyl; or

(ii) any two of R⁸, R⁹ and R¹⁰ form an aryl, aromatic ring,heteroaromatic ring, carbocyclic or heterocyclic ring, which issaturated or unsaturated, containing from about 3 to about 16 members,preferably 3 to about 10 members, more preferably 5 to 7 members that issubstituted with one or more substituents, each substituent beingindependently selected from Z; the other of R⁸, R⁹ and R¹⁰ is selectedas from the groups set forth for R⁹ and R¹⁰ in (i); and the heteroatomsare NR¹¹, O, or S, with the proviso that Ar² is not5-halo-3-loweralkylbenzo[b]thienyl, 5-halo-3-loweralkylbenzo[b]furyl,5-halo-3-loweralkylbenzo[b]pyrrolyl.

In these embodiments, Ar² is, thus, represented by the formulae (IVA andIVB):

that can be substituted at any or all positions or is an analog ofcompounds of formula (IV) in which the substituents form fused aromatic,aliphatic or heterocyclic rings; and in which X is NR¹¹, O, or S, andR¹¹, which is hydrogen or contains up to about 30 carbon atoms,preferably 1 to 10, more preferably 1 to 6, and is selected as definedabove. R⁸, R⁹, R¹⁰ are selected as described above.

In the embodiments provided herein, when R⁸, R⁹ and R¹⁰ are selected asin (i), above, R⁸ is preferably selected from among(CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸,CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸, —(CH₂)_(x)C(O)—W-aryl or—(CH₂)_(x)C(O)—W-heteroaryl-(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸, with the proviso that if R⁸ is(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, or(CH₂)_(r)R¹⁸, and R¹⁸ is phenyl, the phenyl group is substituted atleast two positions, preferably, at least one of those positions isortho, and more preferably it is substituted at four positions; and W isas defined above.

In preferred of these compounds, R¹⁸ is aryl or heteroaryl, preferablyhaving 5 or 6 members in the ring, more preferably phenyl orpyrimidinyl, most preferably phenyl. R⁹ and R¹⁰ are preferably hydrogen,halide, loweralkyl, or halo loweralkyl

The more preferred compounds provided herein are compounds in which thealkyl, alkynyl and alkenyl portions are straight or branched chains,acyclic or cyclic, and have from about 1 up to about 10 carbons; incertain of the more preferred embodiments they have from 1-6 carbons,and they can have fewer than 6 carbons. The aryl, homocyclic andheterocyclic groups can have from 3 to 16, generally, 3-7, more often5-7 members in the rings, and may be single or fused rings. The ringsize and carbon chain length are selected such that the resultingmolecule exhibits activity as an endothelin antagonist or agonist asevidenced by in vitro or in vivo tests, particularly the testsexemplified herein.

In any of the above preferred embodiments: R¹ and R² are preferablyselected independently from alkyl, lower alkenyl, lower alkynyl, lowerhaloalkyl, halide, pseudohalide and H, except that R² is not halide orpseudohalide, and in preferred embodiments is also not higher alkyl.

In preferred embodiments: X is S, O, NR¹¹ in which R¹¹ is aryl,hydrogen, or loweralkyl, preferably, a substituted or unsubstitutedaryl, particularly phenyl, preferably unsubstituted or substituted withloweralkyl or halogen hydrogen or loweralkyl; R¹ is hydrogen, halide,pseudohalide, loweralkyl or lower haloalkyl, most preferably halide; R²is hydrogen, loweralkyl or lower haloalkyl.

The aryl groups are unsubstituted or is substituted with groups such asalkyl, alkoxy, alkoxyalkyl, halogen, alkylenedioxy, particularlymethylene dioxy, amino, nitro and other such groups. The alkylsubstituents are preferably loweralkyl, more preferably containing 1-3carbons.

In more preferred embodiments, two of R⁹ and R¹⁰ are hydrogen, halide orloweralkyl and R⁸ is C(O)NHR¹⁸ or C(O)CH₂R¹⁸ in which R¹⁸ is a phenylgroup that is substituted at least two positions, most preferably atleast one substitutent at the ortho position and also 3,4 or 4,5alkylenedioxy substituents. In more preferred of these embodiments X isS.

In all embodiments, R¹ is preferably halide, H, CH₃ or C₂H₅, and R² isH, CH₃, C₂H₅, C₂F₅ or CF₃. In yet more preferred embodiments, R¹preferably Br, Cl or CH₃; R² is H, CH₃, C₂H₅, or CF₃.

In other embodiments two of R⁸, R⁹ and R¹⁰ form a ring so that AR² isbenzo[b]thienyl, benzo[b]furyl, or indolyl, with the proviso that thereis one or more substituents and they are other than 5-halo and3-loweralkyl, and the other of R⁸, R⁹ and R¹⁰ is selected from aryl,(CH₂)_(r)R¹⁸, C(O)R¹⁸, CO₂R¹⁸, NR¹⁸R¹⁹, SH, S(O)_(n)R¹⁸ in which n is0-2, HNOH, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸. Ar² may be furthersubstituted with any of the groups set forth for R⁸, R⁹ and R¹⁰, and arepreferably selected from among alkyl, alkoxy, alkoxyalkyl, aryl,alkylaryl, aminoalkyl, arylamino, aryl-substituted amino, and NR¹¹.

In embodiments in which ET_(B) antagonists are desired, it is preferredthat R⁸ and R¹⁰ are H or loweralkyl and R⁹ includes heterocyclic oraromatic ring of preferably from 3 to 14, more preferably, 5 to 7,members in the ring. In particular, if X is S, R⁸ and R¹⁰ are H orloweralkyl, and R⁹, includes an aryl group, particularly a substitutedphenyl, such as a 2-loweralkyl substituent. The aryl portion issubstituted with groups such as alkyl, alkoxy, alkoxyalkyl, halogen,alkylenedioxy, particularly methylenedioxy, amino, nitro and other suchgroups. The alkyl substituents are preferably loweralkyl, morepreferably containing 1-3 carbons.

If X is NR¹¹, then R¹¹ is aryl, particularly unsubstituted phenyl orsubstituted phenyl, such as isopropylphenyl.

Other preferred compounds, which are ET_(B) active, are those in whichAr² has formula IVB in which R⁹ is aryl or Z-substituted aryl,particularly phenyl, and Z is loweralkyl or loweralkoxy.

In all embodiments of all of the compounds herein R¹ is preferablyhalide or loweralkyl, most preferably Br, and the compounds are, withreference to formulae IV, 2- or 3-sulfonamides, particularly thiophenesulfonamides.

In certain embodiments provided herein, Ar² is a benzo[b]thienyl,benzo[b]furyl or indolyl (benzo[b]pyrrolyl) group and the compoundsprovided herein are preferably benzo[b]thienyl-, benzo[b]furyl- orindolylsulfonamides. Benzo[b]thiophene, benzo[b]furyl and indolyl 2- or3-sulfonamides are among the compounds preferred herein. Thebenzo[b]-thiophene, benzo[b]furyl and indolyl 2- or 3-sulfonamidesprovided herein are selected with the proviso that the benzene group hasat least one substituent and that substituent is other than 5-halo and3-loweralkyl.

Compounds of particular interest include those of formula III in whichAr² is a phenyl-, benzothienyl, benzofuryl or indolyl [benzopyrrolyl]group or in which Ar² is a substituted phenylaminocarbonylthienyl,substituted phenylaminocarbonylfuryl, substituted aminocarbonylpyrrolylgroup in which there are at least two substituents or Ar² isphenylacetylthiophene, phenylacetylfuran, or phenylacetylpyrrole, is anacetoxystyrylthiophene, acetoxystyrylfuran or acetoxystyrylpyrrole.

The most preferred compounds provided herein have an IC₅₀ for ET_(A)receptors in the assays exemplified herein less than 0.1 μM, morepreferably less than 0.01 μM, and more preferably less than 0.001 (see,e.g., Table 1 for representative experimental results), when measured at4° C., as described in the Examples. When measured at 24° C., the IC₅₀concentrations are somewhat higher (2- to 10-fold; see, Table 1 for somecomparative values).

Among the preferred compounds of interest herein are those in which Ar²has formula VI:

in which M is (CH₂)_(m)C(O)(CH₂)_(r), (CH₂)_(m)C(O)NH(CH₂)_(r),(CH₂)_(m)(CH═CH)(CH₂)_(r), (CH₂)_(m)C(O)(CH₂)_(s)NH(CH₂)_(r),(CH₂)_(m)(CH═CH)(CH₂)_(r), C═N(OH)(CH₂)_(r),(CH₂)_(m)C(O)(CH═CH)_(s)NH(CH₂)_(r), CH(OH)(CH₂)_(r),CH(CH₃)C(O)(CH₂)_(r), CH(CH₃)C(O)(CH₂)_(m)(CH═CH)(CH₂)_(r), (CH₂)_(r),(CH₂)_(r)O, C(O)O, in which m,s and r are each independently 0 to 6,preferably 0 to 3, more preferably M is (CH₂)_(m)C(O)(CH₂)_(r),(CH₂)_(m)C(O)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),(CH₂)_(m)C(O)(CH₂)_(s)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),C═N(OH)(CH₂)_(r), CH(OH)(CH₂)_(r), (CH₂)_(r), (CH₂ 0 _(r)O, C(O)O;

R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from (i) or(ii) as follows:

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected fromamong H, OH; NHR³⁸, CONR³⁸R³⁹, NO₂, cyano, halide, pseudohalide, alkyl,alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino,alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl,alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenyl sulfinyl,alkenyisulfonyl, alkoxycarbonyl, arylaminocarbonyl, alkylaminocarbonyl,aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl, carboxyalkyl,carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl,acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl,(acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, aminoacids, hexoses, O-glycosides, riboses, lower alkyl, CN,—(CH₂)_(x)C(O)(CH₂)_(x), —(CH₂)_(x), (CH₂)_(x)N-lower alkyl,—(CH₂)_(x)C(O)NH₂, a D-, L- or racemic amino acid, a primary orsecondary amide, O-glycoside, a hexose or ribose, —S(O)₂NH₂, hydroxy,alkoxy, alkoxycarbonyl, acetoxyalkyl, —(CH₂)_(x)COOH; —(CH₂)_(x)COOH—,CO₂-lower alkyl, CN, heteroaryl, —COC(O)(CH₂)_(x)CH₃, —(CH₂)_(x)N(CH₃)₂,a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, C(O)NHR⁵⁰,—(CH₂)_(x)OH, —C(O)N(H)N(H)M, or;

(ii) at least two of R³¹, R³², R³³, R³⁴ and R³⁵, which substituteadjacent carbons on the ring, together form alkylenedioxy,alkylenethioxyoxy or alkylenedithioxy (i.e. —O—(CH₂)_(n)—O—,—S—(CH₂)_(n)—O—, —S—(CH₂),—S—, where n is 1 to 4, preferably 1 or 2, )which is unsubstituted or substituted by replacing one or more hydrogenswith halide, loweralkyl, loweralkoxy or halo loweralkyl, and the othersof R³¹, R³², R³³, R³⁴ and R³⁵ are selected as in (i); and

R³⁸ and R³⁹ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl, arylalkyl,arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl,and is preferably hydrogen, loweralkyl, loweralkoxy and lowerhaloalkyl,with the proviso that when M is (CH₂)_(m)C(O)NH(CH₂)_(r), then at leasttwo of R³¹, R³², R³³, R³⁴ and R³⁵ are not hydrogen.

M is most preferably

In general, however, in all of these compounds in which AR² has formulaV or VI or in which R⁸ includes an aryl group, regardless of theselection of M, it is preferred that the aryl substituent have more thanone substituent or at least one substituent in the ortho position. Arylis preferably phenyl that is preferably substituted at the orthoposition and, more preferably at least one additional position,particularly 4 and 6, or adjacent positions, such as 3,4 or 4,5 when thesubsituents are linked to form an alkylenedioxy (or analog thereof inwhich one or both oxygens is(are) replaced with S, or at two additionalpositions, so that it is substituted at the 2, 3, 4 and 6 positions,where the substituents at the 2, 4, and 6 positions are preferably loweralkyl and lower alkoxy and at the 3 position is any of substituents setforth for Z.

In all compounds, at least one of R³¹ and R³⁵ is other than hydrogen.

In more preferred compounds, M is C(O)CH₂, C(O)NH, —CH═CH—,CH₂CH₂C(O)(CH═CH), CH═CHC(O)CH₂, and most preferably has formula VII:

in which W is CH₂ or NH.

M is even more preferably selected from among:

in which R⁴⁰ is preferably hydrogen, alkyl, alkoxy, alkoxyalkyl,haloalkyl, and more preferably loweralkyl, loweralkoxy, or haloloweralkyl, and is more preferably hydrogen or loweralkyl, particularlymethyl or ethyl, and is most preferably hydrogen.

M is most preferably:

In preferred compounds R³¹, R³², R³³, R³⁴ and R³⁵ are selected from (i)or (ii):

(i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected fromloweralkyl, haloloweralkyl, phenyl, alkoxy,loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl,loweralkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy loweralkyl,acetoxy loweralkoxy or loweralkoxycarbonyl; or

(ii) R³² and R³³ or R³³ and R³⁴ form alkylene dioxy, preferablymethylenedioxy, and the others of R³¹, R³², R³³, R³⁴ and R³⁵ areselected as in (i).

In preferred embodiments, R³¹, R³³, R³⁵ are other then hydrogen and arepreferably loweralkyl or lower alkoxy, or R³¹ or R³⁵ is other thanhydrogen, preferably loweralkyl or lower alkoxy, and R³² and R³³ or R³³and R³⁴ form methylenedioxy.

Also of interest herein are compounds that have the formula:

where:

X is S, O or NR¹¹;

each G and R is independently selected from lower alkyl, CN,—(CH₂)_(x)C(O)(CH₂)_(x), —(CH₂)_(x), (CH₂)_(x)N-lower alkyl,—(CH₂)_(x)C(O)NH₂, a D-, L- or racemic amino acid, a primary orsecondary amide, O-glycoside, a hexose or ribose, —S(O)₂NH₂, hydroxy,alkoxy, alkoxycarbonyl, acetoxyalkyl, —(CH₂)_(x)COOH; —(CH₂)_(x)COOH—,CO₂-lower alkyl, CN, heteroaryl, —COC(O)(CH₂)_(x)CH₃, —(CH₂)_(x)N(CH₃)₂, a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl,C(O)NHR⁵⁰, —(CH₂)_(x)OH, —C(O)N(H)N(H)M;

R⁵⁰ is hydrogen, lower alkyl, lower alkoxy;

M is H or R⁵⁰;

R′ is selected from hydrogen, G and R;

W is ═C(halo)₂, ═N(H), —(CH₂)_(x)—, ═N(lower alkyl), —C(O)—, ═C(loweralkyl)₂, and

x is 0-3.

In particular, in these embodiments compounds where: R, G and R′ areselected where the amino acid is L-Asp or L-Glu; the hexose isD-mannose, the heteroaryl is triazolyl, and X is S are of interest. Alsoof interest are compounds in which:

W is ═CH₂, ═NH, ═NCH₃, ═NCH₂CH₃, ═C(CH₃)₂ or CF₂; and

G is —CH₃, —CN, —COCH₃, —CH₂CH₃, —CH₂)_(x)CO₂H are of interest.

Among these compounds are:

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;

N²-(3-cyanomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

methyl-2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylphenyl)acetate;

2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylphenyl)aceticacid;

N²-(3-acetyloxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-hydroxymethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-dimethylaminomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamidetrifluoroacetate;

N²-(3-(4,5-dihydro-1,3-oxazol-2-yl)-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylbenzoicacid;

N-[3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylbenzoyl]glutamicacid;

N-[3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylbenzoyl]asparticacid;

N-[2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylphenyl)acetyl]glutamicacid;

N-[2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylphenyl)acetyl]asparticacid;

N²-(3-cyano-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

2-(3-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-2,4,6-trimethylphenoxy)aceticacid;

N²-(3-alkylsulfonamido-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-arylsulfonamido-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-sulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-alkylsulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-arylsulfamoyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulamoyl)-2-thiophenecarboxamide;

N²-(3-(1H-1,2,3,4-tetraazol-5-ylmethyl)-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-(2-pyridylmethyl)-2,4,6-trimethylphenyl)-3-(4-chloro-3-metlyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-hydrazinocarbonyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-aminomethyl-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

N²-(3-(a-D-mannopyranosyloxymethyl)-2,4,6-trimethylphenyl)-3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thiophenecarboxamide;

5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-cyano-6-methylbenzo[d][1,3]dioxole;

5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-6-cyano-4-methylbenzo[d][1,3]dioxole;

2-(5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-methylbenzo[d][1,3]dioxole)-6-aceticacid;

5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-acetyl-6-methylbenzo[d][1,3]dioxole;

5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-6-acetyl-4-methylbenzo[d][1,3]dioxole;

5-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-7-cyano-4,6-dimethylbenzo[d][1,3]dioxole;

6-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-5,7-dimethylbenzo[d][1,3]dioxole-4-carboxylicacid;

7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-5,6-dimethylbenzo[d][1,3]dioxole-4-carboxylicacid;

7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-cyano-5,6-dimethylbenzo[d][1,3]dioxole;

7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-acetyl-5,6-dimethylbenzo[d][1,3]dioxole;

7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-carboxamido-5,6-dimethylbenzo[d][1,3]dioxole;

7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-aminomethyl-5,6-dimethylbenzo[d][1,3]dioxole; and

7-(3-(4-chloro-3-methyl-5-isoxazolylsulfamoyl)-2-thienylcarboxamido)-4-dimethylaminomethyl-5,6-dimethylbenzo[d][1,3]dioxole;

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-acetoxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide;andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethylphenylaminocarbonyl)thiophene-3-sulfonamide.

In all embodiments, preferred substituents also can be determined byreference to Table 1, which sets forth exemplary compounds. Preferredcompounds are those of Table 1 that have the highest activities, andpreferred substituents are those on the compounds with the highestactivities (activity at the lowest concentration).

TABLE 1 COMPOUND ET_(A) (μM)* ET_(B) (μM)*N-(3,4-dimethyl-5-isoxazolyl)-2- 0.167 16.6methylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.0486 3.5methylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.0067 5.13ethylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-n- 0.0182 ˜1benzylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.0226 ˜3butylbenzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-i- 0.005 5.7propylbenzo[b]thiophene-3-sulfonamide 0.03^(†) 10.7^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-2-n- 0.024 7.95propylbenzo[b]thiophene-3-sulfonamide 0.074^(†) 16.6^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4- 0.048^(†) 1.1^(†)ethylbenzyl)benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4- 0.0015 ± 0.0014 0.324 ± 0.78(methylenedioxy)benzyl]benzo[b]thiophene-3- 0.0074 ± 0.011^(†) 0.939 ±0.262^(†) sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-0.013^(†) 1.2^(†) trimethoxybenzyl)-benzo[b]-thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5- 1.89 ± 0.431^(†) 54.3 ±2.6^(†) methylbenzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4- 0.011 ± 0.005^(†) 0.936 ±0.095^(†) methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4- 0.021 ± 0.017^(†) 2.94 ±1.32^(†) dimethoxybenzyl)benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien- 16^(†) 0.80^(†)2-yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-0.051^(†) 1.5^(†) methoxybenzyl)benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxozolyl)-2-(2- 0.19^(†) 2.2^(†)methoxybenzyl)-benzo[b]thiophene-3-suifonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(4- 0.21^(†) 4.7^(†)chlorobenzyl)benzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(4- 0.041^(†) 1.3^(†)dimethylaminobenzyl)benzo[b]thiophene-3- 0.014 0.477 sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2- 0.15^(†) 22^(†)ethylbenzo[b]furan-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-phenylbenzo 0.932^(†) 46.8^(†)[b]thiophene sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-6-methoxy-2-˜2^(est†) 2.39^(†) [3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methyl-0.0055^(†) 0.364^(†) enedioxy)benzyl]benzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2- 0.631 53.2methoxycarbonylthiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-4-(4- 0.962^(†) 0.435^(†)propylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3- 0.0801^(†) 3.68^(†)(phenylthio)thiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl))-3-0.163 >100 (phenylaminocarbonyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)amino- 0.00116 2.93carbonyl]thiophene-3-sulfonamide 0.0105^(†) 14^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- 8.69 0.363methoxyphenyl)thiophene-2-sulfonamide 26.3^(†) 2.4^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3- 3.26 0.776methoxyphenyl)thiophene-2-sulfonamide 23.4^(†) 4.7^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3- 4.49 0.380thienyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-0.651 7.15 methylthiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3- 0.16 10.77(phenethyl)thiophene-2-sulfonamide 0.676^(†) 37.2^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-4- 6.64 3.97(phenethyl)thiophene-2-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(4-methylphenyl)- 0.00336 11.3aminocarbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-4- 1.40 ˜100phenylthiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.18816.0 [(methyl)phenylaminocarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(α- 0.337 9.37hydroxybenzyl)thiophene-3-sulfonamideN-(4-bromo-5-methyl-3-isoxazolyl)-5-(4- 7.10 0.3593methylphenyl)thiophene-2-sulfonamide 15.8^(†) 0.25^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5- 3.53 0.417phenylthiophene-2-sulfonamide 36.6^(†) 2.4^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4- 6.39 0.0835(trifluoromethyl)phenyl]thiophene-2-sulfonamide 6.31^(†) .282^(†)N,N′-bis{3-[(4-bromo-3-methyl-5- 0.0692 0.290isoxazolyl)aminosulfonyl)thien-2-yl}urea 0.295^(†) 1.19^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-2- 0.160 44.1(hydroxymethyl)thiophene-3- sulfonamide 1.55^(†) --N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2- 3.46 0.529formylphenyl)thiophene-3-sulfonamide 12.31^(†) 1.28 ± 0.71^(†)N,N′-bis{3-[3,4-dimethyl-5- 1.01 ± 1.03 3.7 ± 2.7isoxazolyl)aminosulfonyljthien-2-yl}urea 2.7^(†) 5.9^(†)N-(3,4-dimethyl-5-isoxazolyl))-2-[(3- 0.214 5.34methoxyanilino)methyl]thiophene-3-sulfonamide 0.933^(†) 7.7^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3- 0.537 1.07aminophenyl)thiophene-2-sulfonamide 1.44^(†) 2.63^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5- 0.794 12.0bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide 5.9^(†) 15.5^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3- 1.12 24.0dimethylbutyn-1-yl)thiophene-2-sulfonamide 7.24^(†) 35.5^(†)N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2- 0.381 1.097methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(2- 0.432 0.313tolyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-0.062^(†) >100^(†) carboxyphenyl)aminocarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[2- 0.21^(†) 20^(†)carboxylphenyl)aminocarbonyl]-thiophene-3- sulfonamideN-(4-bromo-3-rnethyl-5-isoxazolyl)-2- 0.84^(†) >100^(†)(aminocarbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino-1-naphthyl)sulfonyl- 0.97^(†) 3.9^(†)aminocarbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2- 17^(†) 0.21^(†)thienyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.017^(†) 9.8^(†)methylenedioxyphenyl)aminocarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.0073^(†) 6.0^(†)methylenedioxy)phenoxycarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4- 0.50^(†) 79^(†)methylenedioxy)phenyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4- 8.1^(†) 3.2^(†)methylenedioxy)benzyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3- 1.6^(†) 39^(†)benzylthiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-15^(†) 4.2^(†) tolyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.27^(†) 7.7^(†)methylenedioxy)benzyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 2.0^(†) 15^(†)methylenedioxy)benzoyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyt)-2-[(2- 0.013^(†) 38^(†)hydroxyphenyl)aminocarbonyl]thiophene-3- sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[3,4- 6.1^(†) >˜50^(†)(methylenedioxy)phenoxycarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethylthien-2- 24^(†) 7.7^(†)yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-0.089^(†) 37^(†) methylenedioxy)benzoyl[aminocarbonyl]thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0065^(†)7.4^(†) (methylenedioxy)phenoxycarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(1- 29^(†) 5.6^(†)pentynyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethylthien-2- 12^(†) 0.71^(†)yl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazotyl)-2-[(3,4-0.0091^(†) 5.5^(†) methylenedioxy)phenylacetyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4- 0.087^(†) 5.9^(†)(methylenedioxy)phenoxycarbonylamino]thiophene- 3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4- 13^(†) 0.76^(†)methylenedioxy)phenoxymethyt]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-(3,4- 0.14^(†) 1.4^(†)methylenedioxy)cinnamyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)- 14^(†) 1.4^(†)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3- 26^(†)4.5^(†) nitrophenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.57^(†) 1.3^(†)methylenedioxy)phenylureido]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4- 0.021^(†) 6.5^(†)(methylenedioxy)phenylacetyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- >100^(†) 17^(†)methyoxycarbonylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- >100^(†) 31^(†)carboxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4- 28^(†) 8.6^(†)tolyl)aminocarbonyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(2- 32^(†) 7.5^(†)methyfuranyl)thiophene-2-sulfonamideN-(4-chloro-3-methy(-5-isoxazolyl)-2-[3,4- .42^(†) 12^(†)(methylenedioxy)benzyloxycarbonyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(3,4- .23^(†) 6.2^(†)methylenedioxyphenyl)]ethoxycarbonyl-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4-(3,4- 20^(†) >˜100^(†)methylenedioxybenzyl)piperazin-1- yl]carbonyl}thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2- 14^(†) 6.2^(†)aminothiophene-3-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-5- 12^(†)9.0^(†) (benzyloxymethyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-cyano-1- 2.1^(†) 27^(†)[(3,4-methylenedioxy)phenyl]acetyl}thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4- 0.21^(†) 9.2^(†)methylenedioxy)phenethyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3- 1.4^(†) 60^(†)dimethylamino)phenoxycarbonyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2- 77^(†) ˜100^(†)sulfonamide N-(4-chloro-3-methyl-5-isoxozolyl-2- 0.44^(†) 34^(†)(cyclohexyloxycarbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[13-hydroxy(3,4- 0.053^(†) 16^(†)methylenedioxy)phenylethyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxyl-1- 0.59^(†) 104^(†)methylindole-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazoIyl)-2-[(4-1.37^(†) — oxacyclohexyl)oxycarbonyl]thiophene-3-sulfonamideN-2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3- 1.8^(†) 32.5^(†)sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)-(2-[3,4-(methyl- — —enedioxy)phenyl]acetyl}thiophene-3-sulfonamide oximeN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 31.3^(†) 14.7^(†)tolyl)aminocarbonyl]-1-methylindole-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 0.023^(†) 15^(†)methoxyphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-1-13,4-(methyl- 5.29^(†) 18.6^(†)enedioxy)benzyl]indole-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 122^(†) 9.7^(†)methylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy- 0.043^(†) 10.1^(†)phenyl)acetyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4- 1.64^(†) 22.8^(†)methylphenoxy) methyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 1.2^(†) 15^(†)methylphenoxy)methyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl- 0.94^(†) 0.66^(†)trans-styryl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl- 0.347^(†) 9.4^(†)phenethyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl- 0.198^(†) 9.13^(†)phenyl)acetyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3- 0.030^(†) 19.1^(†)methoxyphenyl)acetyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl- 6.1^(†) 2.09^(†)phenethyl)-5-(4-tolyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 4.69^(†) 1.56^(†)methylbenzyl)-5-(4-tolyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl- 6.9^(†) 1.58^(†)trans-styryl)-5-(4-tolyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[β,β- 0.128^(†) 2.09^(†)(ethylenedioxy)-3,4-(methylenedioxy)phenethyl]thiophene- 3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[13-(dimethyl- 20.9^(†) ˜100^(†)amino)-3,4-(methylenedioxy)phenethy]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{α-hydroxy- 2.5^(†) 30^(†)[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(5-methyl-3- 0.056^(†) 92^(†)isoxazolyl)aminocarbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-hydroxyl-6- 0.066^(†) 81.3^(†)pyridazinyl)aminocarbonyl]thiophene-3-sulfonamideM-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5- 0.010^(†) 31.6^(†)(methylenedioxy)phenyl]aminocarbonyl}thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-{[3,4- 0.513^(†) 9.6^(†)(methylenedioxy)phenoxy]methyl}thiophene-2- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 0.26^(†) 0.413^(†)methyl)(cinnamyl)]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5- 0.55^(†) --dimethoxy-2-methoxycarbonylphenyl) aminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl- 0.13^(†) --1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)2-{[4,5- 3.80^(†) -- dimethoxy-2,4,5-dimethoxy-2-methoxycar- bonyl)phenyl]phenylaminocarbonyl}thiophene-3-sulfonamide N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxyl- 1.43^(†) —4,5-(methylenedioxy)phenyl]aminocarbonyl}thio- phene-3-sulfonamideM-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4- 0.236^(†) 18^(†)(methylenedioxy)phenethyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4- 0.218^(†) 10^(†)(methylenedioxy)-trans-styryl]thiophene-2- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)- 0.106^(†) 40.1^(†)phenethyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-{[2-acetyl-4,5- 0.032^(†) --(methylenedioxy)phenyl]aminocarbonyl}thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-methoxy-2- 0.027^(†) 0.14^(†)methylphenyl)aminocarbonyljthiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5- 0.0039^(†) 12.2^(†)dimethoxyphenyl)aminocarbonyl]thiophene-3- sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylphenyl)- .0027^(†)29.2^(†) thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylene- 0.0273^(†) 12.2^(†)dioxy)phenylacetyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4- 0.158^(†) 63.1^(†)dimethoxyphenyl)aminocarbonyljthiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6- 0.023^(†) 43.7^(†)pyridyl)aminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hydroxy-4- .006^(†) —methylphenyl)aminocarbonyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-cyano-4,5- 0.0034^(†) 40.4^(†)(methylenedioxy)phenyl]aminocarbonyl}thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0030^(†) 355^(†)(methylenedioxy)phenylaminocarbonyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2- 0.011^(†) 61^(†)carboxamido-4,5-dimethoxyphenylamino- carbonyl)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-(2,4- 0.0027^(†) 17.4^(†)dimethylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl- 0.0004^(†) 4.8^(†)phenylacetyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4- 0.0008^(†)** 3.6^(†)dimethylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0073^(†) 9.2^(†)(methylenedioxy)]phenylaminocarbonyl-3- thiophenesulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0032^(†) 9^(†)(methylenedioxy)phenylacetyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0045^(†) 25.7^(†)(methylenedioxy)-6-(2-acetoxyethyl)phenylamino-carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- 0.0056^(†) 16.8^(†)(methylenedioxy)-6-(2-hydroxyethyl)phenyl-aminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl- 0.045^(†) 17.7^(†)phenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5- 0.007^(†) 18^(†)dimethylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- 0.0068^(†) 19.8^(†)methanesulfonylaminomethyl)-4,5-(methylenedioxy)phenylaminocarbonyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- 0.0038^(†) 25^(†)cyanomethyl-4,5-(methylenedioxy)-6-cyanomethyl]-phenylaminocarbonyl-3-thiophenesulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hyroxyproyl- 0.0073^(†) 8.3^(†)4,5-(methylenedioxy)phenylaminocarbonyl]- thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5- ˜0.1^(†)** ˜6^(†)**(methylenedioxy)cinnamyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5- ˜0.1^(†)** 5^(†)**(methylenedioxy)phenethyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-{[2-propyl-4,5- ˜0.2^(†)**˜1.5^(†)** (methylenedioxy)phenoxy]methyl}thiophene-2- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- ˜0.02^(†)** ˜18^(†)(methylenedioxy)-6-(2-acetoxyethoxy)]phenylamino-carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4- ˜0.01^(†)** ˜18^(†)(methylenedioxy)-6-(2-hydroxyethoxy)phenyl-aminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano-4,5- ˜0.3^(†)** ˜0.7^(†)(methylenedioxy)phenylacetyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-{2- 0.009^(†) 13.8^(†)[(dimethylamino)carbonylmethyl]-4,5-(methylene-dioxy)phenylaminocarbonyl}thiophene-3- sulfonamideN-(4-chloro-3-methy-5-isoxazoIyl)-2-[2-methyl-4,5- 0.794^(†) 6.49^(†)(methylenedioxy)phenylhydroxylmino]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0619^(†) 8.90^(†)(methylenedioxy)phenethyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[2- 0.0795^(†) 3.24^(†)(hydroxymethyl)-4,5- (methylenedioxy)cinnamyllthiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-{2-[(tetrahydro- 0.0967^(†) 4.144H-pyran-2-yloxy)methyl]-4,5-(methylenedioxy)cinnamyl}thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4- 0.1006^(†) 4.30^(†)dimethylphenethyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4- 0.180^(†) 2.97^(†)dimethylcinnamyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4- 0.166^(†) 2.97^(†)dimethylcinnamyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(2,4- 0.346^(†) 7.45^(†)dimethylphenoxy)methyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4- 0.308^(†) 4.48^(†)dimethylphenoxy)methyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-5- 28.1^(†) 60.6^(†)(phenylaminocarbonyl)thiophene-2-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[βacetoxy-2- 0.00544 3.74^(†)methyl-4, 5-(methylenedioxy)styryl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,3,4- 0.000169^(†) 12.5^(†)trimethoxy-6-cyano)phenylaminocarbonyl]thiophene- 3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2- 6.33^(†) 8.82^(†)(cyano)phenyl]benzo[b]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methyl- 0.550^(†) 52.6^(†)enedioxy)phenyl]benzo[b]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.324^(†) 55.1^(†)tolyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-0.832^(†) 21.2^(†) tolyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2- 0.302^(†) 31% @ 100^(†)tolyl)thiophene-2-sulfonamide N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-0.334^(†) ** methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(3- 1.32^(†) 56.3^(†)methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2- 1.71^(†) 59.1^(†)methoxyphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.184 43.9^(†)ethylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.0873 8.48^(†)propylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.218 28.3^(†)isopropylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.160 6.11^(†)butylphenyl)thiophene-2-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.00328^(†) 34.3^(†)(methylenedioxy)phenylacetyl]thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6- 0.000626^(†) 8.27^(†)trimethylphenylaminocarbonyl)thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6- 0.000238^(†) 3.82^(†)trimethylphenylacetyl)thiophene-3-sulfonamideN-(4-chloro-5-methyl-3-isoxazolyl)-2-[2-methyl-4,5- 0.000625^(†)3.69^(†) (methylenedioxy)phenylacetyl]thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5- 0.0804^(†) 3.28^(†)(methylenedioxy)cinnamyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4- 0.0555^(†) 3.48^(†)dimethylphenethyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 0.000266^(†) 9.78^(†)methoxycarbonyl-2,6-dimethyl)-phenylaminocarbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2- 4.41^(†) 31% @ 100^(†)(phenoxycarbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2- 2.71^(†) 20% @ 100^(†)(phenoxycarbonyl)thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-{[3,4- 3.61^(†) 30% @ 100^(†)(methylenedioxy)phenoxy]carbonyl}thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2- 0.684^(†) 105^(†)methylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3- 1.20^(†) 111^(†)methylphenoxy)carbonyt]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4- 0.291^(†) 43.2^(†)dimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2- 0.761^(†) 29% @ 100^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3- 0.79^(†) 90^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4- 1.73^(†) 111^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(4- 5.88^(†) 13% @ 100^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(4- 2.5^(†) 33% @ 100^(†)methoxylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4- 3.2^(†) 43% @ 100^(†)methylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4- 0.648^(†) 68.5^(†)dimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4- 0.274^(†) 21% @ 100^(†)dimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazotyl)-2-{[2-propyl-4,5- 0.138^(†) 11.9^(†)(methylenedioxy)phenoxy]carbonyl}thiophene-3- sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.000321^(†) 16.5^(†)methoxycarbonyl-2,4,6-trimethylphenylamino- 0.00092^(†) --carbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4- 0.100^(†) 60.3^(†)dimethylphenyl)thiophene-2-sulfonamide N-(3,4-dimethyl-5-isoxazolyl)-2-2.85^(†) 31%^(†) (phenoxycarbonyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4- 0.0823^(†) 2.76^(†)isobutylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso- 0.155^(†) 3.31^(†)pentylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(2,4,6- 0.0457^(†) 4.68^(†)trimethylphenoxy)methyl]thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6- 0.0562^(†) 3.39^(†)trimethylphenoxy)methyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4,6- 0.0490^(†) 1.86^(†)trimethylcinnamyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4- 0.0468^(†) 3.63^(†)propylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-butyl-2- 0.0468^(†) 1.66^(†)methylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-pentyl-2- 0.107^(†) 2.40^(†)methylphenyl)thiophene-2-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-{[3,4- 0.302^(†) 6.61^(†)(methylenedioxy)phenoxy)methyl}thiophene-3- sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-{[4,5- 0.107^(†) 0.407^(†)(methylenedioxy)-2-propylphenoxy]methyl} thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4,6- 0.0417^(†) 1.23^(†)trimethylphenethyl)thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4,6- 0.055^(†) 1.62^(†)trimethylphenethyl)thiophene-2-sulfonamideN-(3,4-dimethyl-5-isoxazolyl)-2-[(2,4,6- 0.537^(†) 8% @ 100^(†)trimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6- 0.0776^(†) 30.2^(†)trimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6- 0.479^(†) 24.5^(†)trimethylphenoxy)carbonyl]thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.0006^(†) ˜45^(†)cyanomethyl-2,4,6-trimethylphenylamino- carbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.0015^(†) ˜>100^(†)carboxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.0006^(†) >>100^(†)acetoxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3- 0.0004^(†) ˜80^(†)hydroxymethyl-2,4,6-trimethylphenylamino-carbonyl)thiophene-3-sulfonamide *results are generally the average of 2to 5 experiments **preliminary results or results in which one or moredata points were only determined approximately ^(†)assay performed withincubation at 24° C. As described in the Examples, incubation at thehigher temperature reduces the activity by a factor of 2- to about10-compared to the activity at 4° C. --data not available or measured as% inhibition @ 100 μM % = % inhibition @ 100 μM

It is understood that 4-bromo or 4-chloro groups can be replaced byother 4-halo substituents or other suitable substituents for R¹, such asalkyl.

B. Preparation of the compounds

The preparation of some of the above and other compounds that possessthe requisite activities are set forth in the Examples. Compounds whosesynthesis is not explicitly exemplified can be synthesized by routinemodification of one or more methods described in detail in the Examplesby substituting appropriate readily available reagents.

The preparation of the above compounds are described in detail in theexamples. Any such compound or similar compound may be synthesizedaccording to a method discussed in general below and set forth in theExamples by selecting appropriate starting materials as exemplified.

In general, most of the syntheses involve the condensation of a sulfonylchloride with an aminoisoxazole in dry pyridine or in tetrahydrofuran(THF) and sodium hydride. The sulfonyl chlorides and aminoisoxazoleseither can be obtained commercially or synthesized according to methodsdescribed in the Examples or using other methods available to those ofskill in this art (see, e.g., U.S. Pat. Nos. 4,659,369, 4,861,366 and4,753,672).

The N-(alkylisoxazolyl)sulfonamides can be prepared by condensing anaminoisoxazole with a sulfonyl chloride in dry pyridine with or withoutthe catalyst 4-(dimethylamino)pyridine. TheN-(3,4-dimethyl-5-isoxazolyl)sulfonamides andN-(4,5-dimethyl-5-isoxazolyl) sulfonamides can be prepared from thecorresponding aminodimethylisoxazole, such as5-amino-3,4-dimethylisoxazole. For example, N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide wasprepared from 2-methoxycarbonylthiophene-3-sulfonyl chloride and5-amino-3,4-dimethylisoxazole in dry pyridine.

The N-(4-haloisoxazolyl)sulfonamides can be prepared by condensation ofamino-4-haloisoxazole with a sulfonyl chloride in THF with sodiumhydride as a base. For example,N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide was preparedfrom 5-amino-4-bromo-3-methylisoxazole and thiophene-2-sulfonyl chloridein THF and sodium hydride.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and5-(3-isoxazolyl)thiophene-2-sulphonyl chloride.

Alternatively, compounds, such as those in which Ar² is thienyl, furyland pyrrolyl herein, may be prepared by reacting an appropriate sulfonylchloride with a 5-aminoisoxazole substituted at the 3 and 4 positions,such as 5-amino-4-bromo-3-methylisoxazole, in tetrahydrofuran (THF)solution containing a base, such as sodium hydride. Following thereaction, the THF is removed under reduced pressure, the residuedissolved in water, acidified and extracted with methylene chloride. Theorganic layer is washed and then dried over anhydrous magnesium sulfate,the solvents are evaporated and the residue is purified byrecrystallization using hexanes/ethylacetate to yield pure product.

These sulfonamides also can be prepared from the corresponding sulfonylchloride and the aminoisoxazole in pyridine with or without a catalyticamount of 4-dimethylaminopyridine (DMAP). In some cases, thebis-sulfonyl compound is obtained as the major or exclusive product. Thebis-sulfonated products can be readily hydrolyzed to the sulfonamideusing aqueous sodium hydroxide and a suitable co-solvent, such asmethanol or tetrahydrofuran, generally at room temperature. For example:

(a)N-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamidewas prepared fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide andaniline and 1-ethyl-3′-[3-dimethylaminopropyl]carbodiimide (EDCI).N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared from 4-methoxyaniline, N,N′-diisopropylethylamine andN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzylaminocarbonyl)-thiophene-3-sulfonamidewas prepared fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide andbenzylamine as described above.

N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide wasprepared fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide,which was prepared from the condensation of5-amino-4-bromo-3-methylisoxazole and2-(carbomethoxy)thiophene-3-sulfonyl chloride.

(b)N-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-1-(4′-isopropylphenyl)pyrrole-3-sulfonamidewere prepared from 5-amino-4-bromo-3-methylisoxazole and a mixture of1-(4′-isopropylphenyl)pyrrole-2-sulfonyl chloride and1-(4′-isopropylphenyl)pyrrole-3-sulfonyl chloride. These sulfonylchlorides were prepared from 1-(4′-isopropylphenyl)pyrrole-2-sulfonicacid in phosphorus oxychloride and phosphorus pentachloride.1-(4′-isopropylphenyl)pyrrole-2-sulfonic acid was prepared from1-(4′-isopropylphenyl)pyrrole and chlorosulfonic acid.1-(4′-isopropylphenyl)pyrrole was prepared from 4-isopropylaniline and2,5-dimethoxytetrahydrofuran.

Prodrugs and other derivatives of the compounds suitable foradministration to humans may also be designed and prepared by methodsknown to those of skill in the art (see, e.g., Nogrady (1985) MedicinalChemistry A Biochemical Approach, Oxford University Press, New York,pages 388-392).

Compounds described herein have been synthesized and tested for activityin vitro assays and, in some cases, in vivo animal models. Nuclearmagnetic resonance spectroscopic (NMR), mass spectrometric, infraredspectroscopic and high performance liquid chromatographic analysesindicated that the synthesized compounds have structures consistent withthose expected for such compounds and are generally at least about 98%pure. All of the compounds exemplified or described herein exhibitedactivity as endothelin antagonists.

C. Evaluation of the bioactivity of the compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possess anybiological activities of an endothelin peptide or the ability tointerfere with or inhibit endothelin peptides. Compounds that exhibit invitro activities, such as the ability to bind to endothelin receptors orto compete with one or more of the endothelin peptides for binding toendothelin receptors can be used in the methods for isolation ofendothelin receptors and the methods for distinguishing thespecificities of endothelin receptors, and are candidates for use in themethods of treating endothelin-mediated disorders.

Thus, other preferred compounds of formulas I and II, in addition tothose specifically identified herein, that are endothelin antagonists oragonists may be identified using such screening assays.

1. Identifying compounds that modulate the activity of an endothelinpeptide

The compounds are tested for the ability to modulate the activity ofendothelin-1. Numerous assays are known to those of skill in the art forevaluating the ability of compounds to modulate the activity ofendothelin (see, e.g., U.S. Pat. No. 5,114,918 to Ishikawa et al.; EP A10 436 189 to BANYU PHARMACEUTICAL CO., LTD. (Oct. 7, 1991); Borges etal. (1989) Eur. J. Pharm. 165: 223-230; Filep et al. (1991) Biochem.Biophys. Res. Commun. 177: 171-176). In vitro studies may becorroborated with in vivo studies (see, e.g., U.S. Pat. No. 5,114,918 toIshikawa et al.; EP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD. (Oct.7, 1991)) and pharmaceutical activity thereby evaluated. Such assays aredescribed in the Examples herein and includes the ability to compete forbinding to ET_(A) and ET_(B) receptors present on membranes isolatedfrom cell lines that have been genetically engineered to express eitherET_(A) or ET_(B) receptors on their cell surfaces.

The properties of a potential antagonist may be assessed as a functionof its ability to inhibit an endothelin induced activity in vitro usinga particular tissue, such as rat portal vein and aorta as well as ratuterus, trachea and vas deferens (see e.g., Borges, R., Von Grafenstein,H. and Knight, D. E., “Tissue selectivity of endothelin,” Eur. J.Pharmacol 165:223-230, (1989)). The ability to act as an endothelinantagonist in vivo can be tested in hypertensive rats, ddy mice or otherrecognized animal models (see, Kaltenbronn et al. (1990) J. Med. Chem.33:838-845, see, also, U.S. Pat. No. 5,114,918 to Ishikawa et al.; andEP A1 0 436 189 to BANYU PHARMACEUTICAL CO., LTD (Oct. 7, 1991); see,also Bolger et al. (1983) J. Pharmacol. Exp. Ther. 225291-309). Usingthe results of such animal studies, pharmaceutical effectiveness may beevaluated and pharmaceutically effective dosages determined. A potentialagonist may also be evaluated using in vitro and in vivo assays known tothose of skill in the art.

Endothelin activity can be identified by the ability of a test compoundto stimulate constriction of isolated rat thoracic aorta (Borges et al.(1989) “Tissue selectivity of endothelin” Eur. J. Pharmacol. 165:223-230). To perform the assay, the endothelium is abraded and ringsegments mounted under tension in a tissue bath and treated withendothelin in the presence of the test compound. Changes in endothelininduced tension are recorded. Dose response curves may be generated andused to provide information regarding the relative inhibitory potency ofthe test compound. Other tissues, including heart, skeletal muscle,kidney, uterus, trachea and vas deferens, may be used for evaluating theeffects of a particular test compound on tissue contraction.

Endothelin isotype specific antagonists may be identified by the abilityof a test compound to interfere with endothelin binding to differenttissues or cells expressing different endothelin-receptor subtypes, orto interfere with the biological effects of endothelin or an endothelinisotype (Takayanagi et al. (1991) Reg. Pep. 32: 23-37, Panek et al.(1992) Biochem. Biophys. Res. Commun. 183: 566-571). For example, ET_(B)receptors are expressed in vascular endothelial cells, possiblymediating the release of prostacyclin and endothelium-derived relaxingfactor (De Nucci et al. (1988) Proc. Natl. Acad. Sci. USA 85:9797).ET_(A) receptors are not detected in cultured endothelial cells, whichexpress ET_(B) receptors.

The binding of compounds or inhibition of binding of endothelin toET_(B) receptors can be assessed by measuring the inhibition ofendothelin-1-mediated release of prostacyclin, as measured by its majorstable metabolite, 6-keto PGF_(1a), from cultured bovine aorticendothelial cells (see, e.g., Filep et al. (1991) Biochem. and BiophysRes. Commun. 177:

171-176). Thus, the relative affinity of the compounds for differentendothelin receptors may be evaluated by determining the inhibitory doseresponse curves using tissues that differ in receptor subtype.

Using such assays, the relative affinities of the compounds for ET_(A)receptors and ET_(B) receptors have been and can be assessed. Those thatpossess the desired properties, such as specific inhibition of bindingof endothelin-1, are selected. The selected compounds that exhibitdesirable activities may be therapeutically useful and are tested forsuch uses using the above-described assays from which in vivoeffectiveness may be evaluated (see, e., U.S. Pat. No. 5,248,807; U.S.Pat. No. 5,240,910; U.S. Pat. No. 5,198,548; U.S. Pat. No. 5,187,195;U.S. Pat. No. 5,082,838; U.S. Pat. No. 5,230,999; published CanadianApplication Nos. 2,067,288 and 2071193; published Great BritainApplication No. 2,259,450; Published International PCT Application No.WO 93/08799; Benigi et al. (1993) Kidney International 44:440-444; andNirei et al. (1993) Life Sciences 52:1869-1874). Compounds that exhibitin vitro activities that correlate with in vivo effectiveness will thenbe formulated in suitable pharmaceutical compositions and used astherapeutics.

The compounds also may be used in methods for identifying and isolatingendothelin-specific receptors and aiding in the design of compounds thatare more potent endothelin antagonists or agonists or that are morespecific for a particular endothelin receptor.

2. Isolation of endothelin receptors

A method for identifying endothelin receptors is provided. In practicingthis method, one or more of the compounds is linked to a support andused in methods of affinity purification of receptors. By selectingcompounds with particular specificities, distinct subclasses of ETreceptors may be identified.

One or more of the compounds may be linked to an appropriate resin, suchas Affi-gel, covalently or by other linkage, by methods known to thoseof skill in the art for linking endothelin to such resins (see, Schvartzet al. (1990) Endocrinology 126: 3218-3222). The linked compounds can bethose that are specific for ET_(A) or ET_(B) receptors or other subclassof receptors.

The resin is pre-equilibrated with a suitable buffer generally at aphysiological pH (7 to 8). A composition containing solubilizedreceptors from a selected tissue are mixed with the resin to which thecompound is, linked and the receptors are selectively eluted. Thereceptors can be identified by testing them for binding to an endothelinisopeptide or analog or by other methods by which proteins areidentified and characterized. Preparation of the receptors, the resinand the elution method may be performed by modification of standardprotocols known to those of skill in the art (see, eg., Schvartz et al.(1990) Endocrinology 126: 3218-3222).

Other methods for distinguishing receptor type based on differentialaffinity to any of the compounds herein are provided. Any of the assaysdescribed herein for measuring the affinity of selected compounds forendothelin receptors may also be used to distinguish receptor subtypesbased on affinity for particular compounds provided herein. Inparticular, an unknown receptor may be identified as an ET_(A) or ET_(B)receptor by measuring the binding affinity of the unknown receptor for acompound provided herein that has a known affinity for one receptor overthe other. Such preferential interaction is useful for determining theparticular disease that may be treated with a compound prepared asdescribed herein. For example, compounds with high affinity for ET_(A)receptors and little or no affinity for ET_(B) receptors are candidatesfor use as hypertensive agents; whereas, compounds that preferentiallyinteract with ET_(B) receptors are candidates for use as anti-asthmaagents.

D. Formulation and administration of the compositions

Effective concentrations of one or more of the sulfonamide compounds offormula I or II or pharmaceutically acceptable salts, esters or otherderivatives thereof are mixed with a suitable pharmaceutical carrier orvehicle. In instances in which the compounds exhibit insufficientsolubility, methods for solubilizing compounds may be used. Such methodsare known to those of skill in this art, and include, but are notlimited to, using cosolvents, such as dimethylsulfoxide (DMSO), usingsurfactants, such as tween, or dissolution in aqueous sodiumbicarbonate. Derivatives of the compounds, such as salts of thecompounds or prodrugs of the compounds may also be used in formulatingeffective pharmaceutical compositions.

The concentrations or the compounds are effective for delivery of anamount, upon administration, that ameliorates the symptoms of theendothelin-mediated disease. Typically, the compositions are formulatedfor single dosage administration.

Upon mixing or addition of the sulfonamide compound(s), the resultingmixture may be a solution, suspension, emulsion or the like. The form ofthe resulting mixture depends upon a number of factors, including theintended mode of administration and the solubility of the compound inthe selected carrier or vehicle. The effective concentration issufficient for ameliorating the symptoms of the disease, disorder orcondition treated and may be empirically determined.

Pharmaceutical carriers or vehicles suitable for administration of thecompounds provided herein include any such carriers known to thoseskilled in the art to be suitable for the particular mode ofadministration. In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients.

The active compounds can be administered by any appropriate route, forexample, orally, parenterally, intravenously, intradermally,subcutaneously, or topically, in liquid, semi-liquid or solid form andare formulated in a manner suitable for each route of administration.Preferred modes of administration include oral and parenteral modes ofadministration.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in known in vitro and in vivo systems (see, e.,U.S. Pat. No. 5,114,918 to Ishikawa et al.; EP A1 0 436 189 to BANYUPHARMACEUTICAL CO., LTD (Oct. 7, 1991); Borges et al. (1989) Eur. J.Pharm. 165: 223-230; : Filep et al. (1991) Biochem. Biophys. Res.Commun. 177: 171-176) and then extrapolated therefrom for dosages forhumans.

The concentration of active compound in the drug composition will dependon absorption, inactivation and excretion rates of the active compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to treat the symptoms of hypertension. Theeffective amounts for treating endothelin-mediated disorders areexpected to be higher than the amount of the sulfonamide compound thatwould be administered for treating bacterial infections.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 0.1 ng/ml to about50-100 μg/ml. The pharmaceutical compositions typically should provide adosage of from about 0.01 mg to about 2000 mg of compound per kilogramof body weight per day. The active ingredient may be administered atonce, or may be divided into a number of smaller doses to beadministered at intervals of time. It is understood that the precisedosage and duration of treatment is a function of the disease beingtreated and may be determined empirically using known testing protocolsor by extrapolation from in vivo or in vitro test data. It is to benoted that concentrations and dosage values may also vary with theseverity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions, and that the concentration rangesset forth herein are exemplary only and are not intended to limit thescope or practice of the claimed compositions.

If oral administration is desired, the compound should be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

Oral compositions will generally include an inert diluent or an ediblecarrier and may be compressed into tablets or enclosed in gelatincapsules. For the purpose of oral therapeutic administration, the activecompound or compounds can be incorporated with excipients and used inthe form of tablets, capsules or troches. Pharmaceutically compatiblebinding agents and adjuvant materials can be included as part of thecomposition.

The tablets, pills, capsules, troches and the like can contain any ofthe following ingredients, or compounds of a similar nature: a binder,such as microcrystalline cellulose, gum tragacanth and gelatin; anexcipient such as starch and lactose, a disintegrating agent such as,but not limited to, alginic acid and corn starch; a lubricant such as,but not limited to, magnesium stearate; a glidant, such as, but notlimited to, colloidal silicon dioxide; a sweetening agent such assucrose or saccharin; and a flavoring agent such as peppermint, methylsalicylate, and fruit flavoring.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, chewing gum orthe like. A syrup may contain, in addition to the active compounds,sucrose as a sweetening agent and certain preservatives, dyes andcolorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action, such as antacids, H2 blockers, and diuretics. Forexample, if the compound is used for treating asthma or hypertension, itmay be used with other bronchodilators and antihypertensive agents,respectively.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol or other syntheticsolvent; antimicrobial agents, such as benzyl alcohol and methylparabens; antioxidants, such as ascorbic acid and sodium bisulfite;chelating agents, such as ethylenediaminetetraacetic acid (EDTA);buffers, such as acetates, citrates and phosphates; and agents for theadjustment of tonicity such as sodium chloride or dextrose. Parenteralpreparations can be enclosed in ampules, disposable syringes or multipledose vials made of glass, plastic or other suitable material.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof. Liposomalsuspensions, including tissue-targeted liposomes, may also be suitableas pharmaceutically acceptable carriers. These may be prepared accordingto methods known to those skilled in the art. For example, liposomeformulations may be prepared as described in U.S. Pat. No. 4,522,811.

The active compounds may be prepared with carriers that protect thecompound against rapid elimination from the body, such as time releaseformulations or coatings. Such carriers include controlled releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of such formulations are known to those skilled in theart.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Suchsolutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts. The compounds may be formulated as aerosols fortopical application, such as by inhalation (see, e.g, U.S. Pat. Nos.4,044,126, 4,414,209), and 4,364,923, which describe aerosols fordelivery of a steroid useful for treatment inflammatory diseases,particularly asthma).

Finally, the compounds may be packaged as articles of manufacturecontaining packaging material, a compound provided herein, which iseffective for antagonizing the effects of endothelin, ameliorating thesymptoms of an endothelin-mediated disorder, or inhibiting binding of anendothelin peptide to an ET receptor with an IC₅₀ of less than about 10μM, within the packaging material, and a label that indicates that thecompound or salt thereof is used for antagonizing the effects ofendothelin, treating endothelin-mediated disorders or inhibiting thebinding of an endothelin peptide to an ET receptor.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

EXAMPLE 1 N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) indry tetrahydrofuran (THF, 2 ml) was added to a suspension of sodiumhydride (60% dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1ml) at 0-5° C. After stirring at 0-5° C. for 5 min., the reaction wasstirred at room temperature for 10 min to complete the reaction. Thereaction mixture was re-cooled to 0° C. and thiophene-2-sulfonylchloride (200 mg, 1.1 mmol) dissolved in dry THF (2 ml) was addeddropwise. Stirring was continued for 1 h; during this period thereaction mixture slowly attained ambient temperature. THF was removedunder reduced pressure. The residue was dissolved in water (10 ml), thepH was adjusted to 10-11 by adding 5 N sodium hydroxide solution, andwas extracted with ethyl acetate (3×10 ml) to remove the neutralimpurities. The aqueous layer was acidified with concentrated HCl (pH2-3) and extracted with methylene chloride (3×10 ml). The combinedorganic layers was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to giveN-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide. The purematerial was obtained by recrystallization using hexanes/ethyl acetate(110 mg, 34% yield), m.p. 125-127° C.

EXAMPLE 2N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (177 mg, 1.0 mmol) indry THF (2 ml) was added to a suspension of sodium hydride (60%dispersion in mineral oil, 90 mg, 2.2 mmol) in dry THF (1 ml) at 0-5° C.After stirring at 0-5° C. for 5 min, the reaction was warmed to roomtemperature for 10 min to complete the reaction. The reaction mixturewas re-cooled to 0° C., and 5-(3-isoxazolyl)thiophene-2-sulphonylchloride (273 mg, 1.1 mmol), which had been dissolved in dry THF (2 ml),was added slowly. Stirring was continued for 1 h; during this period thereaction mixture slowly attained ambient temperature. THF was removedunder reduced pressure. The residue was dissolved in water (10 ml), thepH was adjusted to 2-3 by adding concentrated HCl, and was extractedwith methylene chloride (3×10 ml). The combined organic layers was driedover anhydrous magnesium sulfate and concentrated under reduced pressureto giveN-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-isoxazolyl)thiophene-2-sulfonamide.The pure material was obtained by recrystallization using hexanes/ethylacetate (160 mg, 41% yield), m.p. 120-123° C.

EXAMPLE 3N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-pyridyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 5-(2-pyridyl)thiophene-2-sulphonylchloride in 40% yield. Purification was achieved by recrystallizationfrom ethyl acetate to give a crystalline solid, m.p. 186-188° C.

EXAMPLE 4N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4,5-dibromothiophene-2-sulfonamide wasprepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 4,5-dibromothiophene-2-sulphonylchloride in 45% yield. Purification was achieved by recrystallizationfrom ethyl acetate/hexanes to give a crystalline solid, m.p. 153-155° C.

EXAMPLE 5N-(4-Bromo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-chloro-3-methylbenzo[b]thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and5-chloro-3-methylbenzo[b]thiophene-2-sulphonyl chloride in 18% yield.Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 153-155° C.

EXAMPLE 6N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-chlorobenzamidomethyl)thiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-chlorobenzamidomethyl)-thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and5-(4-chlorobenzamidomethyl)thiophene-2-sulphonyl chloride in 27% yield.The crude product was passed through a silica gel column usinghexanes/ethyl acetate as eluent. Purification was effected byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 210° C. (dec).

EXAMPLE 7N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(benzenesulfonyl)thiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(benzenesulfonyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and4-benzenesulfonylthiophene-2-sulphonyl chloride in 26% yield.Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 181-184° C.

EXAMPLE 8N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-4-bromo-5-chloro-thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and4-bromo-5-chlorothiophene-2-sulphonyl chloride in 25% yield.Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 143-145° C.

EXAMPLE 9N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichlorothiophene-3-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichlorothiophene-3-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 2,5-dichlorolthiophene-3-sulphonyl chloride in 47% yield. Purification wasachieved by recrystallization from ethyl acetate/hexanes to give acrystalline solid, m.p. 135-138° C.

EXAMPLE 10N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dimethylthiophene-3-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2, 5-dimethylthiophene-3-sulfonamidewas prepared in the same manner as described in Example 1 from5-amino-4-bromo-3-methylisoxazole and 2, 5-dimethylthiophene-3-sulphonylchloride in 55% yield. Purification was achieved by recrystallizationfrom ethyl acetate/hexanes to give a crystalline solid, m.p. 77-80° C.

EXAMPLE 11N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-4,5-dichlorothiophene-2-sulfonamidewas prepared in the same manner as described in Example 1 from5-amino-4-bromo-3-methylisoxazole and 4,5-dichlorothiophene-2-sulphonylchloride in 42% yield. Purification was achieved by recrystallizationfrom ethyl acetate/hexanes to give a crystalline solid, m.p. 135-138° C.

EXAMPLE 12N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3-sulonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dichloro-4-bromothiophene-3-sulfonamidewas prepared in the same manner as described in Example 1 from5-amino-4-bromo-3-methylisoxazole and4-bromo-2,5-dichlorothiophene-3-sulfonyl chloride in 58% yield.Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 146-149° C.

EXAMPLE 13N-(4-Bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]}thiophene-5-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]}thiophene-5-sulfonamidewas prepared in the same manner as described in Example 1 from5-amino-4-bromo-3-methylisoxazole and2-{3-[1-methyl-5-(trifluoromethyl)pyrazolyl]}thiophene-5-sulphonylchloride in 30% yield. Purification was achieved by recrystallizationfrom ethyl acetate/hexanes to give a crystalline solid, m.p. 121-123° C.

EXAMPLE 14 N-(4-Bromo-5-methyl-3-isoxazolyl)thiophene-2-sulfonamide

Thiophene-2-sulfonyl chloride (183 mg, 1 mmol) was added to a solutionof 3-amino-4-bromo-5-methylisoxazole (177 mg, 1 mmol) in dry pyridine(0.5 ml). The reaction mixture was stirred at room temperature for 3 h.Pyridine was removed under reduced pressure and the residue waspartitioned between water and ethyl acetate. The organic layer waswashed with 1N HCl (3×10 ml), brine (10 ml) and dried over anhydrousmagnesium sulfate. Evaporation of the solvents left an oily residuewhich was solidified at −20° C. and then purified by recrystallizationfrom ethyl acetate/hexanes, to give the pure product (51% yield) as atan solid, m.p. 156-158° C.

EXAMPLE 15N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzenesulfonyl)thiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzenesulfonyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and5-benzenesulfonylthiophene-2-sulfonyl chloride in 59% yield.Purification was achieved by recrystallization from ethylacetate/hexanes to give a crystalline solid, m.p. 139-142° C.

EXAMPLE 16N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and2-(carbomethoxy)thiophene-3-sulfonyl chloride in 73% yield. Purificationwas achieved by recrystallization from ethyl acetate/hexanes to give acrystalline solid, m.p. 198-200° C.

EXAMPLE 17N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide(Example 16) (1.5 g, 3.95 mmol) was dissolved in methanol (10 ml).Sodium hydroxide pellets (1 g, 25 mmol) and a few drops of water werethen added. The resultant solution was stirred for 16 h at ambienttemperature. Methanol was removed under reduced pressure. The residuewas diluted with water and was extracted with ethyl acetate (2×10 ml).The aqueous layer was acidified (pH=2) with concentrated hydrochloricacid and was extracted with ethyl acetate (2×60 ml). The combinedorganic layers was dried over anhydrous magnesium sulfate and filtered.Removal of the solvent gaveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide(1.2 g, 82% yield), which was purified by silica gel columnchromatography using ethyl acetate as eluent, m.p. 188-194° C.

EXAMPLE 18N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide

Aniline (0.093 g, 1 mmol) and1-ethyl-3′[3-dimethylaminopropyl]-carbodiimide (EDCI) (0.191 g, 1 mmol)were added toN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide(0.368 g, 1 mmol) that had been suspended in methylene chloride (5 ml)to produce a clear solution. Stirring was continued for 1 h at ambienttemperature. The reaction mixture was diluted with methylene chloride(50 ml) and washed with 3 N hydrochloric acid solution (3×50 ml). Thecombined organic layers was dried over anhydrous magnesium sulfate andfiltered. Removal of the solvent under reduced pressure gaveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide.The crude product thus obtained was purified by column chromatographyusing ethyl acetate as eluent to yield the product (0.32 g, 72% yield,m.p. 168-170° C.

EXAMPLE 19 N-(4-Bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-2-sulfonamide andN-(4-bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-3-sulfonamide

A. 1-(4′-isopropylphenyl)pyrrole

Glacial acetic acid (100 ml) was added to a mixture of4-isopropylaniline (10 ml, 72.4 mmol) and 2,5-dimethoxytetrahydrofuran(9.6 ml, 72.4 mmol) and the resulting mixture was refluxed for 1.5 h.The reaction mixture was allowed to cool and acetic acid was removedunder reduced pressure. The resulting brown syrup was dissolved in ethylacetate (200 ml) and washed with water (2×200 ml). The organic layer wasdried over magnesium sulfate and filtered. Removal of the solvent gave1-(4′-isopropylphenyl)pyrrole (13.28 g, 99% yield) as a brown syrup.

B. 1-(4′-isopropylphenyl)pyrrole-2-sulfonic acid

Chlorosulfonic acid (1.82 ml, 27.08 mmol) was slowly added to a solutionof 1-(4′-isopropylphenyl)pyrrole (5.01 g, 27.08 mmol) in chloroform (100ml) at 0° C. The resulting solution was stirred at 0° C. for 1 h and foran additional 1 h at room temperature. Chloroform was removed underreduced pressure. The resultant brown liquid was diluted with ethylacetate (200 ml) and washed with 1 N sodium hydroxide. The aqueous layerwas then acidified with concentrated hydrochloric acid (pH<1) and thenextracted with chloroform (2×150 ml). The combined organic layers wasdried over magnesium sulfate and was filtered. Removal of the solventgave 1-(4′-isopropylphenyl)pyrrole-2-sulfonic acid as a brown syrup (3g, 42% yield).

C. 1-(4′-isopropylphenyl)pyrrole-2-sulfonyl chloride and1-(4′-isopropylphenyl)pyrrole-3-sulfonyl chloride

Phosphorus pentachloride (4.7 g, 22.64 mmol) was slowly added to asolution of 1-(4′-isopropylphenyl)pyrrole-2-sulfonic acid (3 g, 11.32mmol)in phosphorus oxychloride (8.4 ml, 90.57 mmol). The resultingmixture was heated at 70° C. for 10 h. The reaction mixture was allowedto cool to room temperature, then carefully poured on to crushed ice(500 g) and extracted with chloroform (200 ml). The combined organiclayers was dried over anhydrous magnesium sulfate. This was filtered andremoval of the solvent yielded a 4:1 mixture of1-(4′-isopropylphenyl)-pyrrole-2-sulfonyl chloride and1-[4′-isopropylphenyl)pyrrole-3-sulfonyl chloride (2.5 g, 78%) as abrown oil.

D. N-(4-bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-2-sulfonamide andN-(4-bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-2-sulfonamide andN-(4-bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-3-sulfonamide were prepared in the samemanner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazoleand a mixture of 1-(4′-isopropylphenyl)pyrrole-2-sulfonyl chloride and1-(4′-isopropylphenyl)pyrrole-3-sulfonyl chloride in 65% combined yield.The mixture was subjected to preparative HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-2-sulfonamide (retention time 22.85 min,5% to 95% acetonitrile in water with 0.1% TFA over 30 min period, C₁₈analytical column) and N-(4-bromo-3-methyl-5-isoxazolyl)1-(4′-isopropylphenyl)pyrrole-3-sulfonamide (retention time 24.56 min,5%, to 95% acetonitrile in water with 0.1% TFA over 30 min period, C₁₈analytical column) as oils.

EXAMPLE 20N-(4-Bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide wasprepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 5-bromothiophene-2-sulfonylchloride in 30% yield. Purification was achieved by recrystallizationfrom ethyl acetate/hexanes to give a crystalline solid, m.p. 240° C.(dec).

EXAMPLE 21N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]-thiophene-3-sulfonamide

4-Methoxyaniline (0.246 g, 2 mmol), bromo-tris-pyrrolidinophosphoniumhexafluorophosphate (PyBrop) (0.466 g, 1 mmol) andN,N′-diisopropylethylamine (0.15 ml) were added toN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide(0.368 g, 1 mmol), which had been suspended in methylene chloride (3ml), resulting in a clear solution. Stirring was continued for 24 h atambient temperature. The reaction mixture was diluted with methylenechloride (50 ml) and washed with 3 N hydrochloric acid solution (3×50ml) followed by 5% sodium carbonate solution (2×50 ml). The combinedorganic layers was dried over anhydrous magnesium sulfate and filtered.Removal of the solvent under reduced pressure gaveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide.The crude product thus obtained was purified by column chromatographyusing ethyl acetate as eluent. This was recrystallized from ethylacetate/hexanes to give a crystalline solid, m.p. 202-205° C. (0.08 g,17% yield).

EXAMPLE 22N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 21 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 3-methoxyaniline in 23% yield. The crude product was purified bycolumn chromatography using ethyl acetate as eluent. This wasrecrystallized from ethyl acetate/hexanes to give a crystalline solid,m.p. 200-202° C.

EXAMPLE 23N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared in the same manner, as described in Example 21 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 2-methoxyaniline in 26% yield. The crude product was purified bycolumn chromatography using ethyl acetate as eluent. This wasrecrystallized from ethyl acetate/hexanes to give a crystalline solid,m.p. 74-80° C.

EXAMPLE 24N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl)thiophene-3-sulfonamide

Benzylamine (0.214 g, 2 mmol),benzotriazole-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphate (Bop) (0.442 g, 1 mmol) andN,N′-diisopropylethylamine (0.15 ml) were added toN-(4-bromo-3-ethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide(0.368 g, 1 mmol), which had been suspended in methylene chloride (3ml). The resultant solution was stirred for 14 h at ambient temperature.This was diluted with methylene chloride (50 ml) and washed with 3 Nhydrochloric acid (3×50 ml) followed by 5% sodium carbonate solution(2×50 ml). The combined organic layers was dried over anhydrousmagnesium sulfate and filtered. Removal of the solvent under reducedpressure gaveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-benzylaminocarbonyl)thiophene-3-sulfonamide.The crude product was purified by column chromatography using ethylacetate as eluent. Recrystallization from ethyl acetate/hexanes gave acrystalline solid, m.p. 186-190° C. (0.14 g, 30% yield).

EXAMPLE 25N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-ethylphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 24 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 4-ethylaniline in 31% yield. The crude product was purified bycolumn chromatography using ethyl acetate as eluent. This wasrecrystallized from ethyl acetate/hexanes to give a crystalline solid,m.p. 187-190° C.

EXAMPLE 26N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-biphenyl)aminocarbonyl]-thiophene-3-sulfonamidecompound was prepared in the same manner as described in Example 24 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 4-phenylaniline in 26% yield. The crude product was purified bycolumn chromatography using ethyl acetate as eluent. This wasrecrystallized from ethyl acetate/hexanes to give a crystalline solid,m.p. 205-212° C. (dec).

EXAMPLE 27N-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide

2-Methoxycarbonylthiophene-3-sulfonyl chloride (2.50 g, 10.05 mmol) wasadded to a solution of 5-amino-3,4-dimethylisoxazole(0.98 g, 8.75 mmol)in dry pyridine (5.0 ml). The reaction mixture was stirred at roomtemperature for 16 h. Pyridine was removed under reduced pressure andthe residue was partitioned between water and dichloromethane. Theorganic layer was washed with 1 N HCl (2×50 ml) and dried over anhydrousmagnesium sulfate. Evaporation of the solvents left an oily residue,which, after purification by column chromatography over silica gel (1:1hexanes/ethyl acetate as eluent), yielded 2.20 g (65%) of a brown solid.Further purification was achieved by recrystallization from ethylacetate/hexanes, giving the pure product as a white solid, m.p. 113-116°C.

EXAMPLE 28N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide wasprepared in the same manner as described in Example 17 fromN-(3,4-dimethyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide bybasic hydrolysis in 94% yield. Purification was achieved byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 202-203° C.

EXAMPLE 29N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(N-phenylaminocarbonyl)thiophene-3-sulfonamidewas prepared in the same manner as described in Example 18 fromN-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide in 40%yield. Purification was achieved by recrystallization frommethanol/water to give a crystalline solid, m.p. 176-178° C.

EXAMPLE 30N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonamide

A. 5-bromo-2,2′-bithiophene

N-Bromosuccinimide (NBS, 1.12 g, 6.3 mmol) was added in small portionsto a stirred solution of 1.0 g (6.01 mmol) of 2,2′-bithiophene in 10 mlof glacial acetic acid and 10 ml of chloroform. After stirring for 1 hat room temperature, the mixture was poured into ice-water and extractedinto chloroform (75 ml). The organic layer was washed with aqueoussodium bicarbonate solution, water, and then dried over magnesiumsulfate and evaporated. The residue was subjected to flashchromatography on silica gel using hexane to give 1.3 g (88%) of a lightgreen solid, m.p. 55-56° C.

B. 5-Chlorosulfonyl-2,2′-bithiophene

A stirred solution of 5-bromo-2,2′-bithiophene (1.5 g, 6.1 mmol) in 10ml of dry ether was placed under an argon atmosphere, cooled to −78° C.and 4.3 ml of a 1.7 M solution of t-butyllithium was added over min.Stirring was continued at this temperature for an additional 20 min.Sulfur dioxide gas was then bubbled in at −78° C. until a yellowprecipitate formed. Bubbling of the sulfur dioxide gas was continued foran additional 3 min and was immediately followed by a dropwise additionof N-chlorosuccinimide (NCS, 902 mg, 6.76 mmol) that had been dissolvedin THF. The mixture was warmed to room temperature and stirring wascontinued for an additional 1.5 h. The mixture was then concentrated andthe residue dissolved in ether. The organic layer was washed with water,brine solution and dried over magnesium sulfate. Evaporation of solventleft a pale yellow solid, which was recrystallized from hexane to give700 mg (44%) of a yellow solid, m.p. 63-64° C.

C.N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-thienyl)thiophene-2-sulfonade wasprepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5,2′-bithiophene (300 mg, 1.14 mmol) with5-amino-4-bromo-3-methylisoxazole (183 mg, 1.03 mmol) yielded, afterflash chromatography using 10% MeOH/CHCl₃, 430 mg (94%) of a pale brownsolid, m.p. 210° C.

EXAMPLE 31 N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide

A. Thiophene-3-sulfonyl chloride

A stirred solution of 3-bromothiophene (1.5 g, 9.2 mmol) in 10 ml of dryether was placed under an argon atmosphere and cooled to −78° C. Overthe course of 20 min, a solution of t-butyllithium (5.6 ml of a 1.7 M)was added and stirring was continued at this temperature for anadditional 20 min. Sulfur dioxide gas was then bubbled in at −78° C. andthe solution was warmed to 0° C., whereupon NCS (1.47 g, 12 mmol) in 8ml of THF, was added dropwise. After warming to room temperature,stirring was continued for an additional 1 hour, after which,evaporation of solvents left 1.55 g of a brown oil. Flash chromatographyover silica gel using hexanes yielded 1.24 g (74%) of a yellow oil whichsolidified on standing to give a yellow crystalline solid, m.p. 38-39°C.

B. N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared inthe same manner as described in Example 2 from thiophene-3-sulfonylchloride with 5-amino-4-bromo-3-methylisoxazole in 22% yield.Purification by column chromatography using 10% MeOH/CHCl₃ as eluentgave a pale brown oil.

EXAMPLE 32 N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

A. N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

A solution of 5-bromothiophene-2-sulfonyl chloride (2.75 g, 10 mmol) and5-amino-3,4-dimethylisoxazole (1.07 g, 9.57 mmol) in pyridine containinga catalytic amount of 4-dimethylaminopyridine (DMAP, 10 mg) was stirredat room temperature for a period of 3 h. The solution was heated at 50°C. for an additional 1.5 h to drive the reaction to completion as judgedby TLC. The pyridine was removed under reduced pressure and the residue,after extraction into ethyl acetate, was washed with 1 N HCl (2×25 ml),water (1×25), brine solution, (1×25 ml) and dried over magnesiumsulfate. Evaporation of solvent left a viscous brown gum, which wassubjected to flash chromatography. Elution with 3% methanol hexanes gave246 mg (10%) of pure sulfonamide.

B.N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (680 mg, 2mmol) in dry THF (2 ml) was added to sodium hydride (121 mg of a 60% oildispersion, 3 mmol) in dry THF (1 ml). The resulting suspension wascooled to 0° C. and methoxyethoxymethyl chloride (334 mg, 2.68 mmol) wasadded dropwise via syringe. The solution was warmed to room temperature,and stirring continued overnight. Evaporation of solvent left an oilthat was extracted into ethyl acetate, washed with brine, dried overmagnesium sulfate and evaporated. Flash chromatography of the residue onsilica gel using 10-15% ethylacetate/hexanes yielded 480 mg (56%) of acolorless oil.

C.N-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

Sodium carbonate (2 ml of a 2 M aqueous solution) followed by phenylboronic acid (86 mg, 0.71 mmol) in 2 ml of 95% ethanol were added to asolution ofN-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide(200 mg, 0.47 mmol) and tetrakis (triphenylphosphine) palladium (O) (23mg, 0.02 mmol) in dry benzene (4 ml) under argon. The mixture wasrefluxed for 12 h, diluted with 5 ml of water and extracted into ethylacetate (3×25 ml). The combined organic extracts was washed with brine(1×25 ml), dried and evaporated. The residue was flash chromatographedon silica gel using 25% ethylacetate/hexanes to afford 123 mg (62%) ofthe sulfonamide as a colorless gum.

D. N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide

HCl (3 ml of a 3 N aqueous solution) was added to a solution ofN-(methoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-phenylthiophene-2-sulfonamide(100 mg, 0.24 mmol) in 3 ml of 95% ethanol and the resulting mixture wasrefluxed for 6 h. The mixture was then concentrated, diluted with 5 mlof water, neutralized with saturated aqueous sodium bicarbonate solutionand acidified to pH 4 using glacial acetic acid. The mixture wasextracted with ethyl acetate (2×25 ml) and the combined organic extractwas washed with brine (1×5 ml), dried and evaporated. Flashchromatography of the residue on silica gel using 2% MeOH/CHCl₃ andfurther purification by reverse phase HPLC yielded 33.4 mg (42%) of thepure sulfonamide as a white powder, m.p. 176-178° C.

EXAMPLE 33N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide

A. N-(5-bromothiophene-2-sulfonyl)-pyrrole

Sodium hydride (60% oil dispersion, 191 m.g., 4.78 mmol) was suspendedin dry tetrahydrofuran (2 ml) and the resulting cloudy suspension wascooled to 0° C. in an ice bath. Pyrrole (385 mg, 5.75 mmol) in drytetrahydrofuran (2 ml) was added dropwise over a period of 10 min. Theice bath was removed and the solution was stirred at room temperatureuntil gas evolution ceased (15 minutes), whereupon5-bromothiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) previouslydissolved in tetrahydrofuran (4.0 ml) was added dropwise through a steelcannula. After stirring for 1 h at room temperature, the mixture wasfiltered through Celite. The filter pad was rinsed with tetrahydrofuran,and the filtrate was evaporated, which left a light brown solid that wasrecrystallized from methanol to produce the sulfonamide (821 mg, 74%yield) as a white powder.

B. 4-Ethylphenylboronic acid

A solution of 1-bromo-4-ethyl benzene (2.0 g, 11 mmol) in dry ether (5ml) was added to magnesium turnings (311 mg, 13 mmol), which had beensuspended in dry ether, by dropwise addition. After addition wascomplete, the suspension was refluxed for a period of 15 min, by whichtime nearly all of the magnesium had reacted. The solution was thenadded to trimethyl borate (1.12 g, 11 mmol), previously dissolved inether (5 ml) at −78° C., warmed to room temperature and stirred for 90min. The reaction was quenched by the addition of 10% aqueous HCl (2 ml)and the solution was extracted with ether. The combined ether extractwas extracted with 1 M NaOH (2×20 ml), the aqueous extracts wereacidified with dilute HCl to pH 2 and extracted with ether (2×25 ml).The resulting combined ether extract was washed once with water (10 ml),dried and evaporated to produce a white solid (676 mg, 38% yield), m.p.138-140° C.

C.

N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in thesame manner as described in Example 32C, from 4-ethylphenylboronic acidand N-(5-bromothiophenesulfonyl)pyrrole. Purification by columnchromatography using 10% ethyl acetate/hexanes gave the pure sulfonamideas a tan solid in 81% yield.

D. 5—Chlorosulfonyl-2-(4-ethylphenyl)thiophene

A solution of N-[5-(4-ethylphenyl)thiophene-2-sulfonyl]pyrrole (100 mg,0.32 mmol) and 6 N sodium hydroxide (1 ml) in methanol (1.5 ml) wasrefluxed for approximately 6 h. Evaporation of solvents and drying invacuo resulted in an oil. Phosphorus oxychloride (0.258 ml, 2.52 mmol)and phosphorus pentachloride (131 mg, 0.63 mmol) were added to the oiland the resulting brown suspension was heated at 50° C. for 3 h. Theresulting clear brown solution was carefully added to about 20 ml ofcrushed ice and then extracted with ethyl acetate (3×25 ml). Thecombined organic layers was washed with brine (2×5 ml), dried (MgSO₄)and evaporated to leave an oily residue. Flash chromatography oversilica gel using 2% ethyl acetate/hexanes yielded (53 mg, 59%) of thepure sulfonyl chloride as a pale yellow oil.

E.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethylphenyl)thiophene-2-sulfonamide was prepared in the same manner as described inExample 2. Reaction of 5-chlorosulfonyl-2-(4-ethylphenyl) thiophene(47.1 mg, 0.16 mmol) with 5-amino-4-bromo-3-methyl isoxazole (29 mg,0.16 mmol) yielded, after flash chromatography using 10% MeOH/CHCl₃, apale brown solid (46 mg, 66% yield), m.p. 172-175° C.

EXAMPLE 34 N-(3,4-dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide

A. Benzo[b]thiophene-2-sulfonyl chloride

Benzo[b]thiophene (1.50 g, 11.2 mmol) was stirred at 0° C. in ml of THF.t-Butyllithium (1.7 M, 16.8 mmol, 9.9 ml) was slowly added over a 5minute period. Fifteen minutes later, SO₂ was flushed into the reactionflask and a thick white precipitate formed. The reaction mixture wasstirred for 15 minutes at 0° C. and then NCS (1.64 g, 12.3 mmol) wasadded. The reaction was warmed to 25° C. and stirred for 30 min. It wasthen poured into ethyl acetate (150 ml) and washed with brine (3×100ml). The organic phase was dried with MgSO₄, filtered and concentratedto collect 2.29 g of a brown oil. The brown oil was subjected to flashchromatography (5% ethyl acetate/hexanes), which provided a yellow tansolid (1.39 g, 53% yield).

B. N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]thiophene-2-sulfonamide

3,4-Dimethyl-5-amino-isoxazole (0.224 g, 2.0 mmol) and 50 mg of DMAPwere stirred in 5 ml of pyridine at 25° C. Thebenzo[b]thiophene-2-sulfonyl chloride (0.16 g, 2.6 mmol) was added andthe dark brown-yellow reaction mixture was stirred for 18 h at ambienttemperature, poured into 100 ml of ethyl acetate and washed with 2% HCl(3×50 ml). The organic phase was dried with MgSO₄, filtered andconcentrated to collect 0.61 g of a brown oil/solid. The brown oil/solidwas subjected to flash chromatography (30% ethyl acetate/hexanes) toprovide 0.37 g of a light brown solid. This was stirred in 10 ml ofmethanol and 0.5 g of NaOH. The methanolic solution was heated forreflux for 1 h, then cooled to 25° C. and the methanol was removed invacuo. The resulting residue was acidified to pH 1 with 2% HCl (100 ml)and extracted with ethyl acetate (2×50 ml) The organic phase was driedwith MgSO₄, filtered and concentrated to collect 0.225 g of ayellow-orange solid. This was recrystallized from CHCl₃/hexanes toproduce a light tan-yellow solid (0.194 g, 31% yield), m.p. 157-160° C.

EXAMPLE 35 N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide

A. Benzo[b]furan-2-sulfonyl chloride

Benzo[b]furan-2-sulfonyl chloride was prepared as in Example 34A frombenzo[b]furan (1.61 g, 13.6 mmol), t-BuLi (1.7 M, 17.7 mmol, 10.4 ml)and NCS (2.0 g, 15.0 mmol). Flash chromatography (5% ethylacetale/hexanes) yielded a brown solid (1.84 g, 62% yield).

B. N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide

N-(3,4-Dimethyl-5-isoxazolyl)benzo[b]furan-2-sulfonamide was prepared,in the same manner as described in Example 34B, from3,4-dimethyl-5-amino isoxazole (78 mg, 0.70 mmol) andbenzo[b]furan-2-sulfonyl chloride (0.46 g, 2.1 mmol) Flashchromatography (30% ethyl acetate/hexanes) provided 0.186 g of a lightyellow solid, which was treated with 31 mg of NaOH in 10 ml of methanolat 25° C. for 30 minutes. Recrystallization from CHCl₃/hexanes yielded alight tan solid (90 mg, 44% yield), m.p. 160.5-163° C.

EXAMPLE 36 N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide

A. Furan-2-sulfonyl chloride

Furan-2-sulfonyl chloride was prepared as in Example 34A from furan(0.96 g, 14.2 mmol), t-BuLi (1.7 M, 17 mmol, 10 ml) and NCS (2.27 g, 17mmol) using ether (30 ml) as the solvent. Flash chromatography (5% ethylacetate/hexanes) produced a yellow liquid (1.22 g, 52% yield).

B. N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)furan-2-sulfonamide was prepared asdescribed in Example 34B from 3,4-dimethyl-5-amino isoxazole (0.122 g,1.0 mmol), furan-2-sulfonyl chloride (0.50 g, 3.0 mmol) and NaOH (64mg). Flash chromatography (50% ethyl acetate/hexanes) yielded 70 mg of ayellow solid. Recrystallization from CHCl₃/hexanes produced an off-whitesolid (46 mg, 29% yield), m.p 107-110° C.

EXAMPLE 37 N-(3,4-Dimethyl-5-isoxazolyl)-3-methoxy-2-thiophenesulfonamide

A. 3-methoxy-2-thiophenesulfonyl chloride

Chlorosulfonic acid (ClSO₃H, 2.31 g, 19.62 mmol) was slowly added to asolution of 3-methoxythiophene (2.29 g, 19.62 mmol) in CHCl₃ (80 ml) at0° C. The resulting mixture was stirred at 0° C. for 30 min. The solventwas evaporated under reduced pressure at room temperature, the residuewas suspended in POCl₃ (15 ml, 156.96 mmol), and PCl₅ (8.2 g, 39.24mmol) was added slowly. The reaction was stirred at 60° C. for 18 h,then cooled to room temperature and poured onto crushed ice (200 g). Theaqueous mixture was extracted with CHCl₃ (2×150 ml) and the combinedorganic layers was dried (MgSO₄). The solid was removed by filtrationand the filtrate was concentrated to give 3-methoxy-2-thiophenesulfonylchloride as a brown oil (1.81 g, 43% yield).

B. N-(3,4-.dimethyl-5-isoxazolyl)-3-methoxy-2-thiophene sulfonamide

Sodium hydride (1.02 g, 25.56 mmol, 60% dispersion in mineral oil) wasslowly added to a solution of 3-methoxy-2-thiophenesulfonyl chloride(1.18 g, 8.52 mmol) and 3,4-dimethyl-5-aminoisoxazole (1.05 g, 9.37mmol) in THF (20 ml) at room temperature. The resulting mixture wasrefluxed for 4 h. THF was removed under reduced pressure. The residuewas dissolved in water (10 ml), the pH was adjusted to 10-11 by adding 5N sodium hydroxide solution, and was extracted with ethyl acetate (3×10ml) to remove the neutral impurities. The aqueous layer was acidifiedwith concentrated HCl (pH 2-3) and extracted with methylene chloride(3×10 ml). The combined organic layers was dried over anhydrousmagnesium sulfate to produce a crude oil. Further purification byreverse phase HPLC yielded a yellow oil (retention time 14.94 min, 5% to95% acetonitrile in H₂O with 0.1% TFA over 30 min period, C₁₈ analyticalcolumn).

EXAMPLE 38 N-(4-Bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophenesulfonamide and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophenesulfonamide

A. 3-phenyl-2-thiophenesulfonyl chloride and4-phenyl-2-thiophenesulfonyl chloride

n-Butyllithium (2.38 M, 17.2 ml, 41.03 mmol) was slowly added to asolution of 3-phenylthiophene (5.47 g, 34.2 mmol) in Et₂O (25 ml) at 0°C. The ice bath was removed, the mixture was stirred at room temperaturefor 2 h, cooled to −30° C. (CO₂/acetone) and SO₂ gas was bubbled throughthe reaction mixture for 20 min. A solution of NCS (6.06 g, 44.5 mmol)in THF (20 ml) was then added. The reaction was allowed to warm to roomtemperature and stirred for 16 h. The crude mixture was filtered, andthe solid was washed with Et₂O. The combined organic layers wasconcentrated and the residue was chromatographed (hexanes/CHCl₃) to give3-phenyl-2-thiophenesulfonyl chloride and 4-phenyl-2-thiophenesulfonylchloride as a 1:1 mixture (1.46 g, 16.5%, while solid).

B. N-(4-Bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophene sulfonamideand N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophene sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophene sulfonamide andN-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophene sulfonamide wereprepared as described in Example 1. A fraction of the crude mixture ofproducts was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-3-phenyl-2-thiophene sulfonamide(light brown solid, retention time 20.48 min, 5% to 95% acetonitrile inwater with 0.1% TFA over 30 min C₁₈ analytical column, m.p. 105-107° C.)and N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenyl-2-thiophene sulfonamide(dull yellow solid, m.p. 108-110° C., retention time 21.35 min, sameconditions).

EXAMPLE 394-tert-Butyl-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide

A solution of 5-amino-4-bromo-3-methylisoxazole (354 mg, 2.0 mmol) indry THF (1 ml) was added to a suspension of sodium hydride (60%dispersion in mineral oil, 188 mg, 4.4 mmol) in dry THF (1 ml) at 0-5°C. After stirring at 0-5° C. for 10 min., the reaction was warmed toroom temperature for 10 min. to complete the reaction. The reactionmixture was re-cooled to 0° C. and 4-tert-butylbenzenesulfonyl chloride(512 mg, 2.2 mmol) was added slowly. Stirring was continued for 20 min.at 0-5° C. Excess sodium hydride was decomposed by addition of methanol(0.4 ml) followed by water (0.5 ml). The mixture was acidified withhydrochloric acid and extracted with dichloromethane. The extract wasdried over anhydrous magnesium sulfate and the solvent was removed underreduced pressure to give a crude product, which was purified byrecrystallization from ethyl acetate/hexanes to give a white solid in21% yield, m.p. 170° C. (dec.).

EXAMPLE 40N-(3,4-Dimethyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamide

A. 2-Methylbenzo[b]thiophene

t-BuLi (1.7 M, 26 mmoles, 15 ml) was added to a stirred solution ofbenzo[b]thiophene (17 mmoles, 2.3 g) and THF (30 ml) at −50° C. Theresulting bright yellow reaction mixture was warmed to −30° C., andiodomethane (26 mmoles, 1.6 ml) was added. After 10 min. at −30° C., thesolution was warmed to ambient temperature and stirred an additional 30min., then diluted with ether (100 ml) and washed with brine (2×100 ml).The organic phase was dried (MgSO₄), filtered and concentrated tocollect 2.48 g (98%) of 2-methylbenzo[b]thiophene as a light yellowsolid.

B. 2-Methylbenzo[b]thiophene-3-sulfonyl chloride

Sulfuryl chloride (9.5 mmoles, 0.76 ml) was added to a stirred solutionof dimethylformamide (DMF; 11.2 mmoles, 0.87 ml) at 0° C., and theresulting faint yellow solution was stirred for 20 min at 0° C.2-Methylbenzo[b]thiophene (5.6 mmoles, 0.83 g) was then added, thereaction mixture was diluted with 2 ml of DMF, and then heated to 85° C.After 2.5 hrs at 85° C., the brown reaction mixture was cooled toambient temperature and added to ice (100 ml). The aqueous phase wasextracted with ethyl acetate (100 ml), and the organic phase was dried(MgSO₄), filtered and concentrated to collect an orange-brown solid.Flash chromatography (4% ethyl acetate/hexanes) provided 0.89 g (640%)of 2-methylbenzo[b]thiophene-3-sulfonyl chloride as a yellow solid.

C. N-(3,4-Dimethyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamide

2-Methylbenzo[b]thiophene-3-sulfonyl chloride (1.7 mmoles, 0.41 g) wasadded to a solution of 3,4-dimethyl-5-aminoisoxazole (0.75 mmoles, 84mg), 4-dimethylaminopyridine (DMAP; 50 mg) and pyridine (5 ml) atambient temperature. After 24 h, the reaction mixture was diluted withethyl acetate (50 ml) and washed with 2% HCl (3×50 ml). The organicphase was dried (MgSO₄), filtered and concentrated to collect abrown-orange solid, which was dissolved in a solution of methanol (10ml) and NaOH (60 mg). The solution was stirred 1 h at ambienttemperature, then the methanol was evaporated and the resulting residuewas diluted with 2% HCl (50 ml), and extracted with ethyl acetate (75ml). The organic phase was dried (MgSO₄), filtered and concentrated tocollect a tan solid. Recrystallization from chloroform and hexanesresulted in 93 mg (38%) ofN-(3,4-dimethyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamide aslight yellow crystals, m.p. 174-176° C.

EXAMPLE 41N-(4-Bromo-3-methyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamide

NaH (60% oil dispersion, 2.5 mmoles, 100 mg) was added to a solution of4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g). THF (5 ml) at0° C. was added, and the resulting reaction mixture was stirred 10 minat 0° C. 2-Methylbenzo[b]thiophene-3-sulfonyl chloride (1.2 mmoles, 0.28g) was added, and the reaction mixture was stirred for 20 min at 0° C.,then warmed to ambient temperature for 1 hr followed by addition of 2 mlof water. The mixture was diluted with ethyl acetate (100 ml) and washedwith 2% HCl (2×50 ml), then brine (50 ml). The organic phase was dried(MgSO₄), filtered and concentrated. Recrystallization of the crudereaction mixture resulted in 0.24 g (63%) ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamideas an off-white solid, m.p. 131-133° C.

EXAMPLE 42N-(4-Bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3-sulfonamide

A. 2-Ethylbenzo[b]thiophene

2-Ethylbenzo[b]thiophene was prepared by the method of Example 40A withbenzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 8.9 mmoles, 5.3ml), iodoethane (8.9 mmoles, 0.72 ml) and THF (20 ml). 1.2 g (99%) of ayellow liquid was isolated.

B. 2-Ethylbenzo[b]thiophene-3-sulfonyl chloride

2-Ethylbenzo[b]thiophene-3-sulfonyl chloride compound was prepared bythe method of Example 40B with dimethylformamide (DMF; 13.6 mmoles, 1.1ml), sulfonyl chloride (11.5 mmoles, 0.93 ml). Flash chromatography (2%ethyl acetate/hexanes) provided 1.34 g (76%) of a light yellow solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 with4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5mmoles, 100 mg), 2-ethylbenzo[b]thiophene-3-sulfonyl chloride (1.2mmoles, 0.31 g) and THF (7 ml). Recrystallization from chloroform andhexanes provided 0.24 g (60%) of a tan crystalline solid, m.p.118.5-120° C.

EXAMPLE 43N-(4-Bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamide

A. 2-Benzylbenzo[b]thiophene

2-Benzylbenzo[b]thiophene was prepared by the method of Example 40A withbenzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles, 6.6ml), benzyl bromide (10.2 mmoles, 1.3 ml) and THF (20 ml). Flashchromatography (hexanes) provided 0.66 g (39%) of a yellow solid.

B. 2-Benzylbenzo[b]thiophene-3-sulfonyl chloride

2-Benzylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the methodof Example 40B with DMF (5.4 mmoles, 0.41 ml), sulfuryl chloride (4.6mmoles, 0.37 ml) and 2-benzylbenzo[b]thiophene. Flash chromatography (5%ethyl acetate/hexanes) provided 0.55 g (64%) of a yellow solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-benzylbenzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 with4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5mmoles, 100 mg), 2-benzylbenzo[b]thiophene-3-sulfonyl chloride (1.2mmoles, 0.39 g) and THF (7 ml). Flash chromatography (5%methanol/chloroform) followed by recrystallization from chloroform andhexanes provided 0.11 g (24%) of a tan crystalline solid, m.p. 120-123°C.

EXAMPLE 44N-(4-Bromo-3-methyl-5-isoxazolyl)-2-butylbenzo[b]thiophene-3-sulfonamide

A. 2-Butylbenzo[b]thiophene

2-n-Butylbenzo[b]thiophene was prepared by the method of Example 40Awith benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles,5.7 ml), 1-bromobutane (9.7 mmoles, 1.0 ml) and THF (20 ml). 0.65 g(46%) of a yellow liquid was isolated.

B. 2-n-Butylbenzo[b]thiophene-3-sulfonyl chloride

2-n-Butylbenzo[b]thiophene-3-sulfonyl chloride was prepared by themethod of Example 40B with DMF (6.6 mmoles, 0.51 ml), sulfuryl chloride(5.6 mmoles, 0.45 ml) and 2-n-butylbenzo[b]thiophene (3.3 mmoles, 0.63g). Flash chromatography (2% ethyl acetate/hexanes) provided 0.68 9(71%) of an orange solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-butylbenzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 with4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5mmoles, 100 mg), 2-n-butylbenzo[b]thiophene-3-sulfonyl chloride (1.2mmoles, 0.35 g) and THF (6 ml). Recrystallization from ethyl acetate andhexanes provided 0.24 g (56%) of a yellow solid, m.p. 124.5-126° C.

EXAMPLE 45N-(4-Bromo-3-methyl-5-isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulfonamide

A. 2-n-propylbenzo[b]thiophene

2-n-Propylbenzo[b]thiophene was prepared by the method of Example 40Awith benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles,5.7 ml), n-bromopropane (9.7 mmoles, 0.88 ml) and THF (20 ml). 1.11 g(85%) of a light yellow liquid was isolated.

B. 2-propylbenzo[b]thiophene-3-sulfonyl chloride

2-Propylbenzo[b]thiophene-3-sulfonyl chloride was prepared by the methodof Example 40B with DMF (3.6 mmoles, 0.28 ml), sulfuryl chloride (3.1mmoles, 0.25 ml) and 2-propylbenzo[b]thiophene (1.8 mmoles, 0.32 g).Flash chromatography (3% ethyl acetate/hexanes) provided 0.28 g (56%) ofa yellow solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-n-propylbenzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 with4-bromo-3-methyl-5-aminoisoxazole (0.68 mmoles, 0.12 g) NaH (1.7 mmoles,6.8 mg), 2-n-propylbenzo[b]thiophene-3-sulfonyl chloride (0.82 mmoles,0.23 g) and THF (3 ml). Recrystallization from chloroform and hexanesprovided 0.19 g (67%) of a yellow crystalline solid, m.p. 136-138° C.

EXAMPLE 46N-(4-Bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfornamide

A. 2-i-propylbenzo[b]thiophene

2-i-Propylbenzo[b]thiophene was prepared by the method of Example 40Awith benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 11.2 mmoles,6.6 ml), 2-iodopropane (11.2 mmoles, 1.12 ml) and THF (20 ml) withstirring at ambient temperature for 24 hrs. It was isolated as a yellowoil (1.11 g; 85% yield).

B. 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride

2-i-propylbenzo[b]thiophene-3-sulfonyl chloride compound was prepared bythe method of Example 40B with DMF (5.2 mmoles, 0.40 ml), using sulfurylchloride (4.2 mmoles, 0.34 ml) and 2-i-propylbenzo[b]thiophene (2.1mmoles, 0.37 g). Flash chromatography (1% ethyl acetate/hexanes)provided 0.17 g (29%) of a yellow solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-i-propylbenzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 using4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 97 mg), NaH (1.4 mmoles,5.5 mg), 2-i-propylbenzo[b]thiophene-3-sulfonyl chloride (0.60 mmoles,0.17 g) and THF (2 ml). Recrystallization from chloroform and hexanesprovided 89 mg (39%) of a tan crystalline solid, m.p. 157.5-159° C.

EXAMPLE 47N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(4ethylbenzyl)benzo[b]-thiophene-3-sulfonamide

A. a-(2-benzo[b]thiophene)-4-ethylbenzyl alcohol

a-(2-Benzo[b]thiophene)-4-ethylbenzyl alcohol was prepared by the methodof Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (9.7mmoles, 1.7 M, 5.7 ml), 4-ethylbenzaldehyde (8.9 mmoles, 1.22 ml) andTHF (20 ml). Flash chromatography (10% ethyl acetate/hexanes) provided1.79 g (89%) of a yellow solid.

B. 2-(4-ethylbenzyl)benzo[b]thiophene

To a solution of a-(2-benzo[b]thiophene)-4-ethylbenzyl alcohol (4.0mmoles, 1.1 g), triethylsilane (4.4 mmoles, 0.11 ml) and CH₂Cl₂ (20 ml)at 0° C. was added TFA (8.1 mmoles, 0.62 ml). The solution was stirredmin at 0° C., then diluted with ether (100 ml) and washed with sat.NaHCO₃ (100 ml). The organic phase was dried (MgSO₄), filtered andconcentrated. Flash chromatography (2% ethyl acetate/hexanes) provided0.69 9 (68%) of a white solid.

C. 2-(4-Ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride

2-(4-Ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride was prepared bythe method of Example 40B with DMF (5.4 mmoles, 0.42 ml), sulfurylchloride (4.6 mmoles, 0.37 ml) and 2-(4-ethylbenzyl)benzo[b]thiophene(2.7 mmoles, 0.69 g). Flash chromatography 12% ethyl acetate/hexanes)provided 0.43 g (45%) of an orange solid.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-ethylbenzyl)benzo[b]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-ethylbenzyl)benzo[b]-thiophene-3-sulfonamidewas prepared by the method of Example 41 using4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5mmoles, 100 mg), 2-(4-ethylbenzyl)benzo[b]thiophene-3-sulfonyl chloride(1.2 mmoles, 0.42 g) and THF (6 ml). Flash chromatography (50% ethylacetate/hexanes) followed by recrystallization from chloroform andhexanes provided 0.21 g (43%) of a tan solid, m.p. 128-130° C.

EXAMPLE 48N-t4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide

A. a-(2-benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol

a-(2-Benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol was prepared bythe method of Example 40A using benzo[b]thiophene (7.5 mmoles, 1.0 g),t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), piperonal (8.9 mmoles, 1.0 g) andTHF (20 ml). Flash chromatography (20% ethyl acetate/hexanes) provided1.6 g (74%) of a yellow solid.

B. 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene

2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene was prepared by themethod of Example 47B usinga-(2-benzo[b]thienyl)-3,4-(methylenedioxy)benzyl alcohol (6.2 mmoles,1.8 g), triethylsilane (6.8 mmoles, 1.1 ml) CH₂Cl₂ (50 ml) and TFA (12.4mmoles, 0.95 ml). Recrystallization from hexanes provided 1.2 g (73%) ofa light orange solid.

C. 2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride

2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride wasprepared by the method of Example 40B using DMF (9.1 mmoles, 0.70 ml),sulfuryl chloride (7.7 mmoles, 0.62 ml) and2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene (4.6 mmoles, 1.2 g).Flash chromatography (5% ethyl acetate/hexanes) provided 0.71 g (42%) ofa light yellow solid.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 using4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.177 g), NaH (2.5mmoles, 100 mg),2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride (1.1mmoles, 0.40 g) and THF (7 ml). Flash chromatography (50% ethylacetate/hexanes) followed by recrystallization from chloroform andhexanes provided 0.23 g (45%) of a tan crystalline solid, m.p. 164-165°C.

EXAMPLE 49N-(4-Bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)benzo-2,1,3-thiadiazole-4-sulfonamidewas prepared from 5-amino-4-bromo-3-methylisoxazole and2,1,3-thiadiazole-4-sulfonyl chloride according to the proceduresdescribed in Example 39. The crude product was purified byrecrystallization from ethyl acetate/hexanes to give a crystallinesolid, m.p. 177-179° C., yield 34%.

EXAMPLE 50N-(4-Bromo-3-methyl-5-isoxazolyl)-1-methylindole-2-sulfonamide

A. 1-Methylindole-2-sulfonyl chloride

1-Methylindole-2-sulfonyl chloride was prepared by the method of Example34 with 1-methylindole (7.8 mmols, 1.0 ml), t-BuLi (1.7 m, 9.4 mmols,5.5 ml), sulfur dioxide, NCS (8.6 mmols, 1.2 g) and THF (15 ml). Flashchromatography (2% ethyl acetate/hexanes) provided 0.66 g (3%) of ayellow solid.

B. N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-1-methylindole-2-sulfonamide wasprepared by the method of Example 41 with4-bromo-3-methyl-5-aminoisoxazole (1.0 mmols, 0.18 g), NaH (2.5 mmols,60 mg), 1-methylindole-2-sulfonyl chloride (1.2 mmols, 0.26 9) and THF(7 ml). Recrystallization from chloroform and hexane provided 0.28 g(77%) of a brown solid, m.p. 132-134° C.

EXAMPLE 51 N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide

A. 2-Dibenzofuransulfonyl chloride

2-Dibenzofuransulfonic acid (12.8 mmol) was heated at 70° C. withphosphorus oxychloride (1.30 ml, 14.0 mmol) for 2 h. Excess phosphorusoxychloride was removed under reduced pressure. The residue wasdecomposed with ice water and extracted with ethyl acetate. The extractwas washed with 5% sodium bicarbonate solution, dried over anhydrousmagnesium sulfate and concentrated to yield 2.9 g crude2-dibenzofuransulfonyl chloride.

B. N-(3,4-Dimethyl-5-isoxazolyl)-2-dibenzofuransulfonamide

The 2-benzofuransulfonyl chloride from step (a) was added to a solutionof 5-amino-3,4-dimethylisoxazole (250 mg, 2.2 mmol) and4-(dimethyl)aminopyridine (5 mg) in dry pyridine (2.0 ml). The reactionmixture was stirred at room temperature for 4 h. Pyridine was removedunder reduced pressure and the residue was partitioned between water andethyl acetate. The organic layer was washed with 1 N HCl (2×25 ml),brine (25 ml) and dried over anhydrous magnesium sulfate. Evaporation ofthe solvents left an oily residue that, after purification by columnchromatography over silica gel (1% methanol in chloroform as eluent),yielded white solid (32% yield). Purification was achieved byrecrystallization from chloroform/hexanes to give a white “cotton-like”solid, m.p. 173-175° C. (dec.).

EXAMPLE 52N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(3,4-methylenedioxy)phenyl]-ethoxycarbonyl-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-(3,4-methylenedioxy)-phenyl]ethoxycarbonyl-3-sulfonamidewas prepared by the same method as described in Example 97 with theexception that 2-(3,4-methylenedioxy)phenylethanol was used instead ofsesamol. The final product was obtained by HPLC purification as ayellowish oil, (500 mg, 25% yield).

EXAMPLE 53N-(4-Bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide

A. 3-bromo-2-phenyl-thiophene

Tetrakis (triphenylphosphine) palladium (400 mg), Na₂CO₃ (4 M, 80 ml,320 mmol) and phenylboric acid (3.81 g, 30.3 mmol) as a solution inethanol (80 ml) were sequentially added to a solution of2,3-dibromothiophene (7.33 g, 30.3 mmol) in benzene (100 ml). Themixture was heated at reflux for 12 hours. The aqueous layer of thecrude mixture was removed and the organic layer was diluted with Et₂O(200 ml), washed with 1 N NaOH (2×150 ml) and was dried (MgSO₂),filtered and the solvent was evaporated. The residue was chromatographedusing hexane as the eluent to give 3-bromo-2-phenylthiophene as a clearoil (3.31 g, 47% yield).

B. 2-Phenylthiophene-3-sulfonylchloride

n-BuLi (2.38 M, 11.5 ml, 27.28 mmol) was slowly added to a solution of3-bromo-2-phenyl-thiophene (22.73 mmol) in ether (50 ml) at 0° C. Thereaction was stirred at 0° C. for 1 h. SO₂ was bubbled through themixture for 15 minutes at 0° C. followed by the addition of NCS (3.95 g,29.55 mmol) as a suspension in THF (20 ml). The crude products werepurified by column chromatography (hexanes) to give2-phenylthiophene-3-sulfonylchloride as a white solid (1.23 g, 34%yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenylthiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-phenyl-thiophene-3-sulfonamide wasprepared from 2-phenyl-3-thiophene sulfonylchloride using the methoddescribed in Example 1. The product was purified by HPLC, 77% yield,reddish solid, mp 86-89° C.

EXAMPLE 543-Phenoxy-N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide

A. 3-Phenoxythiophene.

Cuprous chloride (3.08 g, 31.1 mmol) and phenol (8.78 g, 93.3 mmol) weresequentially added to a solution of 3-bromothiophene (5.06 g, 31.1 mmol)in pyridine (150 ml). Sodium hydride (3.73 g, 93.3 mmol, 60% dispersionin mineral oil) was then slowly added. The reaction was heated at refluxfor 20 hours under Argon. The pyridine was removed under reducedpressure. The residue was diluted with Et₂O (200 ml) and washed with 1 NNaOH (3×100 ml), 1 N HCl (2×150 ml) and 1 N NaOH (150 ml). The organiclayer was dried (MgSO₄), filtered, and the solvent was evaporated. Theresidue was chromatographed using hexanes to give 3-phenoxy-thiophene asa clear oil (4.0 g, 74% yield).

B. 3-Phenoxythiophene-2-sulfonyl chloride

BuLi (2.38 M, 11.5 ml, 27.28 mmol) was slowly added to a solution of3-phenoxythiophene (4.0 g, 22.73 mmol) in ether (50 ml) at 0° C. Thereaction was stirred at 0° C. for 1 h. SO₂ was bubbled through themixture for 15 minutes at 0° C. followed by the addition of NCS (3.95 g,29.55 mmol) as a suspension in THF (20 ml). The mixture was allowed towarm up to 25° C. and stirred for 2 more h. The precipitate wasfiltered, and the filtrate was concentrated and chromatographed(hexanes) to give 3-phenoxythiophene-2-sulfonyl chloride as a yellowishsolid (1.03 g, 17% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenoxythiophene-2-sulfonamide wasprepared from 3-phenoxythiophene-2-sulfonyl chloride and5-amino-4-bromo-3-methylisoxazole using the method described inExample 1. The product was recrystallized from acetonitrile/H₂O to givea solid m.p. 121-123° C., 61% yield.

EXAMPLE 55N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-isopropylphenyl)-aminocarbonyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 24 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 4-isopropylaniline in 19% yield. The crude product was passedthrough silica gel column using ethyl acetate as eluent. This wasfurther purified by HPLC (5% CH₃CN to 100% CH₃CN over 30 min.) to give asolid.

EXAMPLE 56N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-sec-butylphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 24 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 4-sec-butylaniline in 25% yield. The crude product was passedthrough silica gel column using ethyl acetate as eluent. This wasfurther purified by HPLC (5% CH₃CN to 100% CH₃CN over 30 min.) give asolid, m.p. 205-208° C.

EXAMPLE 57N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-tert-butylphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-tert-butylphenyl)-aminocarbonyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 24 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 4-tert-butylaniline in 28% yield. The crude product was passedthrough silica gel column using ethyl acetate as eluent. This wasfurther purified by HPLC (5% CH₃CN to 100% CH₃CN over 30 min.) give asolid, m.p. 76-86° C.

EXAMPLE 58N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(4-butylphenyl)aminocarbonyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(4-butylphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 24 fromN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamideand 4-butylaniline in 18% yield. The crude product was passed throughsilica gel column using ethyl acetate as eluent. This was furtherPurified by HPLC (5% CH₃CN to 100% CH₃CN over 30 min.) give a solid.

EXAMPLE 59 N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide

A. Thiazole-2-sulfonyl chloride

Thiazole (0.51 g, 6 mmol) was dissolved in THF (5 ml) and cooled to −78°C. under argon atmosphere. n-Butyllithium (2.5 M solution in hexane, 2.4ml, 6 mmol) was added dropwise under constant stirring. The resultantreaction mixture was stirred at −78° C. for 40 min. Sulfur dioxide wasbubbled through the reaction mixture for 15 min at −78° C. The reactionmixture was allowed to attain ambient temperature slowly and stirred for30 min. NCS was added and stirring was continued for 30 min. Thereaction mixture was diluted with water (50 ml), extracted with ethylacetate (2×50 ml) and the combined organic layers was dried overanhydrous MgSO₄. Removal of the solvent under reduced pressure gavecrude product which was purified by column chromatography, using hexaneas eluent, to give thiazole-2-sulfonyl chloride as a liquid(0.6 g, 54%yield).

B. N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared inthe same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and thiazole-2-sulfonyl chloride in57% yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CN over 30min.) to give a solid., m.p. 175-177° C.

EXAMPLE 60 N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared inthe same manner as described in Example 2 from5-amino-4-chloro-3-methylisoxazole and thiazole-2-sulfonyl chloride in33% yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CN over 30min.) to give a solid, m.p. 171-173° C.

EXAMPLE 61 N-(3,4-dimethyl-5-isoxazolyl)thiazole-2-sulfonamide

N-(3,4-methyl-5-isoxazolyl)thioazole-2-sulfonamide was prepared in thesame manner as described in Example 14 from5-amino-3,4-dimethylisoxazole and thiazole-2-sulfonyl chloride in 37%yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CN over 30 min.)give a solid, m.p. 118-120° C.

EXAMPLE 625-benzyl-N-(4-Bromo-3-methyl-5-isoxazolyl)thiophene-2-sulfonamide

A. 1-(2-Thienyl)benzyl alcohol

Sodium borohydride (0.37 g, 10 mmol) was added to 2-benzoylthiophene(1.88 g, 10 mmol) dissolved in methanol/THF mixture (1:10 ratio, 11 ml).This was stirred at room temperature for 10 h. The reaction mixture wasdecomposed by addition of saturated ammonium chloride solution (50 ml)and was extracted with ethyl acetate (2×50 ml). The combined organiclayers was dried over anhydrous MgSO₄. Removal of the solvent gave1-(2-thienyl)benzyl alcohol as a solid (1.75 g, 92% yield).

B. 2-Benzylthiophene

Acetic anhydride (5 ml) was added to a solution of 1-(2-thienyl)benzylalcohol in pyridine. The resultant solution was stirred at 70° C. for3h. Water (50 ml) was added and the reaction mixture was stirred at roomtemperature for 2h. This was extracted with ethyl acetate (2×50 ml) andthe combined organic layers dried over anhydrous MgSO₄. Removal of thesolvent gave crude product, which was purified by passing through silicagel using 3:1 hexane/ethyl acetate mixture to give 1-(2-thienyl)benzylacetate.

A solution of 1-(2-thienyl)benzyl acetate in THF (5 ml) was added Pgcarefully to dry liquid ammonia (100 ml). Lithium metal was added insmall portions until the blue color persisted. The resulting reactionmixture was stirred for 30 min, and the reaction was quenched byaddition of solid ammonium chloride. The residue, after completeevaporation of liquid ammonia, was dissolved in water (50 ml) and wasextracted with methylene chloride (2×50 ml). The combined organic layerswas dried over MgSO₄ and filtered. Removal of the solvent gave crudeproduct, which was purified by column chromatography using hexane aseluent to give 2-benzylthiophene (1.2 g, 68% yield).

C. 5-Benzylthiophene-2-sulfonyl chloride

To a solution of 2-benzylthiophene (0.875 g, 5 mmol) in chloroform (2ml) at 0° C. was added chlorosulfonic acid dropwise and the reaction wasstirred at 0° C. for 30 min. The reaction mixture was decomposed bypouring onto crushed ice (20 g). The mixture was extracted with ethylacetate, dried over MgSO₄ and filtered. The solvent was removed underreduced pressure to give 5-benzylthiophene-2-sulfonic acid.

Phosphorous pentachloride (2.08 g, 40 mmol) was added to a solution of5-benzylthiophene-2-sulfonic acid in phosphorous oxychloride (6.0 g, 40mmol) at 0° C. The reaction mixture was kept at 50° C. for 1 h, cooledto room temperature, then poured onto crushed ice (50 g) and extractedwith ethyl acetate (2×30 ml). Removal of the solvent under reducedpressure gave a crude product, which was purified by columnchromatography using 3% ethyl acetate in hexane to give2-benzylthiophene-5-sulfonyl chloride (0.6 g, 39% yield).

D. N-(4-bromo-3-methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfonamide

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-benzylthiophene-2-sulfonamide wasprepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 5-benzyl-2-thiophenesulfonylchloride in 22% yield. The product was purified by HPLC (5% CH₃CN to100% CH₃CN over 30 min.) to give a solid, m.p. 49-50° C.

EXAMPLE 63N-(4-Bromo-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide

A. 1-(3-Thienyl)phenethyl alcohol

Benzyl bromide (25.65 g, 150 mmol) was added dropwise over 8 h to asuspension of magnesium (3.6 g, 150 mmol) in ether (75 ml) dissolved inether (30 ml). The resulting mixture was cooled to −10° C.3-thiophenecarboxaldehyde in ether (45 ml) over 30 min was then addedand the resultant reaction mixture was stirred at room temperature for 6h. This was cooled to 0° C. and the reaction mixture was decomposed byaddition of 0.1 N HCl. The ether layer was separated and the aqueousphase was extracted with ethyl acetate (2×50 ml). The combined organiclayers was dried over MgSO₄ and filtered. Removal of the solvent gave1-(3-thienyl)phenethyl alcohol (16 g, 78% yield).

B. 1-(3-Thienyl)phenethyl acetate

1-(3-Thienyl)phenethyl alcohol (10 g, 49 mmol) was dissolved in a 2:1pyridine and acetic anhydride mixture (50 ml). This was stirred at 80°C. for 4 h. Excess of pyridine and acetic anhydride mixture was removedunder reduced pressure and the residue was dissolved in water (100 ml).This was extracted with methylene chloride (3×75 ml) and the combinedorganic layers was dried over MgSO₄ and filtered. Removal of the solventgave 1-(3-thienyl)phenethyl acetate (10.2 g, 84% yield).

C. 3-Phenethylthiophene

1-(3-thienyl)phenylethyl acetate dissolved in THF (20 ml) was addedcarefully to dry liquid ammonia (300 ml). Lithium metal was added insmall portions until the blue color persisted. The resulting reactionmixture was stirred for 30 min and the reaction was quenched by additionof solid ammonium chloride. The residue, after the complete evaporationof liquid ammonia, was dissolved in water (100 ml) and was extractedwith methylene chloride (4×50 ml). The combined organic layers was driedover MgSO₄ and filtered. Removal of the solvent gave a crude product,which was purified by column chromatography using hexane followed bymixture of ethyl acetate in hexane as eluent to give3-phenethylthiophene (3.2 g, 34% yield) and 1-(3-thienyl)phenethylacetate (starting material, 7 g).

D. 3-Phenethylthiophene-2-sulfonyl chloride and4-phenethylthiophene-2-sulfonyl chloride

3-Phenethylthiophene (0.94 g, 5 mmol) was dissolved in THF (12 ml) andcooled to −78° C. under argon atmosphere. n-Butyllithium (2.5 M solutionin hexane, 4.4 ml, 5.5 mmol) was added dropwise with constant stirringunder an argon atmosphere. The resultant reaction mixture was stirred at−10° C. to 0° C. for 3 h, cooled to −78° C. and sulfur dioxide wasbubbled through the reaction mixture for 15 min. The reaction mixturewas allowed to attain ambient temperature slowly and stirring continuedfor 30 min. NCS (1 g) was added and stirring was continued for 1 h. Thereaction mixture was diluted with water (50 ml), extracted withmethylene chloride (2×50 ml) and the combined organic layers was driedover anhydrous MgSO₄. Removal of the solvent under reduced pressure gavea crude product which was purified by column chromatography, using 0.2%ethyl acetate in hexane as eluent, to give3-phenethyl-2-thiophenesulfonyl chloride (0.06 g, 4% yield) and4-phenethyl-2-thiophenesulfonyl chloride (0.72 g, 45% yield).

E. N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-phenethylthiophene-2-sulfonamide wasprepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 3-phenethyl-2-thiophenesulfonylchloride in 48% yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CNover 30 min.) to give a solid.

EXAMPLE 64N-(4-Bromo-3-methyl-5-isoxazolyl)-4-phenethylthiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-phenethylthiophene-2-sulfonamide wasprepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 4-phenethyl-2-thiophenesulfonylchloride in 32% yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CNover 30 min.) to give a gum.

EXAMPLE 65N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide

A. 5-bromothiophene-2-sulfonyl chloride

Chlorosulfonic acid was added dropwise over 20 min. to a cold solution(−78° C.) of 2-bromothiophene (16.3 g, 100 mmol) in methylene chloride(50 ml) was added. After addition of chlorosulfonic acid was complete,the cold bath was removed. The reaction mixture was allowed to attainroom temperature slowly (2 h), was added dropwise onto the crushed ice(1000 g) and was extracted with methylene chloride (4×100 ml). Thecombined organic layers was dried over MgSO₄, filtered and the solventwas removed under reduced pressure to give a crude product. This waspurified by column chromatography using hexane as eluent to give5-bromothiophene-2-sulfonyl chloride (22 g, 75% yield).

B. N-(5-bromothiophene-2-sulfonyl)pyrrole

N-(5-bromothiophene-2-sulfonyl)pyrrole was prepared in the same manneras described in Example 33A from 5-bromothiophene-2-sulfonyl chlorideand pyrrole in 88% yield. This was purified by recrystallization usinghexane/ethyl acetate as a solvent.

C. 3-Methoxyphenylboronic acid

3-Methoxyphenylboronic acid was prepared in the same manner as describedin Example 33B from 3-bromoanisole and triisopropyl borate in 82% yield.This was used in the next step without any further purification.

D. N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in thesame manner as described in Example 32C from 3-methoxyphenylboronic acidand N-(5-bromothiophene-2-sulfonyl)pyrrole in 93% yield. This waspurified by recrystallization using hexane/ethyl acetate as solvent.

E. 5-(3-Methoxyphenyl)thiophene-2-sulfonyl chloride

To a suspension of

N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole (1.4 g, 4.5 mmol) inethanol (15 ml) was added 6 N sodium hydroxide solution (15 ml) and theresultant reaction mixture refluxed for 14 h. The reaction mixture wascooled to room temperature. Ethanol was removed under reduced pressureand the resultant precipitate was filtered and dried under vacuum (1.1g,91% yield).

Phosphorous pentachloride (2.08 g, 10 mmol) was added to the suspensionof sodium slat of sulfonic acid (0.62 g, 2.5 mmol) (obtained from abovestep) in phosphorousoxy chloride (0.93 ml, 10 mmol) and the resultantreaction mixture stirred at room temperature for 3 h. This wasdecomposed by adding on to crushed ice and the product was extractedwith methylene chloride (2×50 ml). The combined organic layers driedover MgSO₄ and filtered. Removal of the solvent gave the crude productwhich was purified by column chromatography using 2% ethyl acetate inhexane to give 5-(3-methoxyphenyl)thiophene-2-sulfonyl chloride (0.51 g,75%).

F.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-methoxyphenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and5-(3-methoxyphenyl)thiophene-2-sulfonyl chloride in 48% yield. This waspurified by HPLC (5% CH₃CN to 100% CH₃CN over 30 min.) give a solid.

EXAMPLE 66N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-methylfuranyl)thiophene-2-sulfonamide

A. N-(pyrrole)-5-(2-methylfuranyl)thiophene-2-sulfonamide

t-BuLi (1.7 m solution in hexane, 7.9 ml, 14.6 mmol) was added dropwiseunder constant stirring under a nitrogen atmosphere to a solution of2-methyl furan (1.0 g, 12 mmol) in THF (20 ml) at −78° C. The solutionwas then warmed to −10° C. and stirring was continued for 45 min. Thesolution was then added to a solution of zinc chloride (27 ml of a 0.5 Msolution in THF) at −30° C. and then warmed to room temperature wherestirring continued for 1 hr. resulting in a pale yellow clear solution.The solution was then transferred via a steel canula under nitrogen to asolution of N-(pyrrole)-5-bromothiophene-2-sulfonamide (Example 33A, 3.5g, 12 mmol) and tetrakis(triphenylphosphine)-palladium (O) (693 mg, 0.6mmol) in THF (15 ml) at −781° C. The solution was then warmed to roomtemperature and stirred for a period of 2 hours. Purification by columnchromatography using 2% ethyl acetate gave 680 mg ofN-(pyrrole)-5-(2-methylfuranyl)thiophene-2-sulfonamide as a pale yellowpowder (19% yield).

B. 2-(2-methylfuranyl)thiophene-5-sulfonyl chloride

2-(2-methylfuranyl)thiophene-5-sulfonyl chloride was prepared in thesame manner as described in Example 33D fromN-(pyrrole)-5-(2-methylfuranyl)thiophene-2-sulfonamide (300 mg, 1.02mmol). Purification by column chromatography using 2% ethylacetate/hexanes gave 145 mg (53%) of the sulfonyl chloride as a paleyellow solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-furanyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-furanyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-(2-methylfuranyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol) with5-amino-4-bromo-3-methyl isoxazole (41 mg, 0.21 mmol), afterpurification by column chromatography using 10% MeOH/CHCl₃, gave 45 mgof the pure sulfonamide as a brown semisolid, 54% yield, m.p. 123-124°C.

EXAMPLE 67N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamide

A. N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in thesame manner as described in Example 32C, from 4-methoxyphenylboronicacid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Recrystallization usinghexane/ethyl acetate gave a solid in quantitive yield.

B. 5-chlorosulfonyl-2-(4-methoxyphenyl)thiophene

A solution of N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl)pyrrole (1.4 g,4.5 mmol) was suspended in ethanol (15 ml). A 6N sodium hydroxidesolution was added, and the resulting suspension was refluxed for 14 hr.to give a clear solution. This was cooled to room temperature. Ethanolwas removed under reduced pressure. A precipitate was formed on standingat room temperature which was filtered and washed with methylenechloride and dried under vacuum giving a solid (1.2 g, 91%).

The solid (0.67 g, 2.5 mmol) was suspended in phosphorous oxychloride(0.92 ml, 10 mmole) and phosphorous pentachloride (2.08 g, 10 mmole) wasadded. The resulting mixture was stirred at room temperature for 3 hr.The reaction mixture was decomposed by pouring onto crushed ice (50 g).The mixture was extracted with methylene chloride (2×50 ml) and thecombined organic layers was dried over MgSO₄. Removal of solvent underreduced pressure gave a crude product which was purified by columnchromatography using 2% EtOAc in hexane as solvent to give5-chlorosulfonyl-2-(4-methoxyphenyl)-thiophene (530 mg, 86%).

C.N-(4-bromo-3-methyl-5-isoxazoly)-5-(4-methoxyphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 1. Reaction of5-chlorosulfonyl-2-(4-methoxyphenyl)thiophene with5-amino-4-bromo-3-methylisoxazole gaveN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxyphenyl)thiophene-2-sulfonamidein 50% yield, m.p. 128-130° C.

EXAMPLE 68N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide

A. 3-Thiopheneboric acid

n-Butyllithium (2.5 M solution in hexane, 20 ml, 50 mmol) was addeddropwise to a solution of 3-bromothiophene (8.15 g, 50 mmol) in THF (20ml) at −78° C. under an argon atmosphere. The resulting solution wasstirred at −78° C. for 45 min, and then added to a solution oftriisopropyl borate (9.4 g, 50 mmol) in THF at −78° C. over 30 minthrough a steel cannula. The resulting reaction mixture was stirred atroom temperature for 12 h and was decomposed by the addition of 100 ml 1N HCl. The aqueous layer was extracted with ether (2×100 ml) and thecombined organic layers was extracted with 1 M NaOH (3×30 ml), theaqueous extract was acidified with concentrated HCl to pH 2 andextracted with ether (3×50 ml). The combined ether extract was washedonce with water, dried over MgSO₄ and filtered. Removal of the solventgave 3-thienylboronic acid as a solid (5.2 g, 80% yield).

B. N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrole

N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in the samemanner as described in Example 32C from 3-thienylboronic acid and

N-(5-bromothiophene-2-sulfonyl)pyrrole in quantative yield. This waspurified by recrystallization using hexane/ethyl acetate as solvent.

C. 5-(3-Thienyl)thiophene-2-sulfonyl chloride

5-(3-thienyl)thiophene-2-sulfonyl chloride was prepared in the samemanner as described in Example 65E from

N-[5-(3-thienyl)thiophene-2-sulfonyl]pyrrole in 74% yield.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-thienyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from5-amino-4-bromo-3-methylisoxazole and 5-(3-thienyl)thiophene-2-sulfonylchloride in 40% yield. This was purified by HPLC (5% CH₃CN to 100% CH₃CNover 30 min.) give a solid.

EXAMPLE 69 N-(4-Bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide was prepared by themethod of Example 1 with 5-amino-4-bromo-3-methylisoxazole (0.266 g, 1.5mmol), NaH (60% oil dispersion) (0.15 g, 3.8 mmol) and furan-2-sulfonylchloride (Example 36A) (0.30 mg, 1.8 mmol). Flash chromatography (50%EtOAc/hexane) and recrystallization from CHCl₃ and hexane provided 90 mg(20% yield) of light yellow crystals (m.p. 117-119° C.).

EXAMPLE 70N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide

A. 2-(phenylthio)furan

t-BuLi (1.7 M, 10 ml, 17 mmol) was added to a solution of furan (1.24ml, 17 mmol) in 20 ml of THF at −60° C. Thirty minutes laterdiphenyldisulfide (3.7 g, 17 mmol) was added via cannula in 8 ml of THF.The reaction was warmed to ambient temperature for 30 minutes, thendiluted with 150 ml of ether and washed with 3% NaOH (3×100 ml). Theorganic was dried (MgSO₄), filtered and concentrated to collect 2.92 g(97% yield) of a light yellow liquid.

B. 5-phenylthiofuran-2-sulfonyl chloride

5-phenylthiofuran-2-sulfonyl chloride was prepared by the method ofExample 34A with 5-phenylthiofuran (1.5 g, 8.5 mmol), t-BuLi (1.2 m, 8.9mmol, 5.3 ml) and NCS (1.14 g, 8.5 mmol). Flash chromatography (5%EtOAc/hexane) provided 1.61 g (69% yield) of a yellow-orange liquid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide wasprepared by the method of Example 1 with4-bromo-3-methyl-2-aminoisoxazole (0.354 g, 2.0 mmol), NaH (60% oildispersion) (0.20 g, 5.0 mmol) and 5-phenylthiofuran-2-sulfonyl chloride(0.66 g, 2.4 mmol). Flash chromatography (50% EtOAc/hexane) andrecrystallization from CHCl₃/hexane provided 82 mg (10% yield) of a tansolid (m.p. 90-91.5° C.).

EXAMPLE 71 N-(4-Bromo-3-methyl-5-isoxazolyl)-5-phenylfuran-2-sulfonamide

A. 2-Phenylfuran

2-phenylfuran was prepared by the method of Example 32C from2-bromofuran (0.93 g, 6.3 mmol), sodium carbonate (18 ml of 2 M aqueoussolution), phenyl boric acid (0.93 g, 7.6 mmol) and tetrakis(triphenylphosphine) palladium (O) (0.36 g, 0.32 mmol). Flashchromatography with hexane provided 0.79 g (87% yield) of a colorlessliquid.

B. 5-phenylfuran-2-sulfonyl chloride

5-phenylfuran-2-sulfonyl chloride was prepared by the method of Example34A with 2-phenylfuran (0.79 g, 5.5 mmol), t-BuLi (1.7 m, 6.0 mmol, 3.6ml) and NCS (0.73 g, 5.5 mmol). Flash chromatography (5% EtOAc/hexane)provided 0.84 g (63% yield) of a light red solid.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuran-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-phenylfuran-2-sulfonamide wasprepared by the method of Example 1 with 4-bromo-3-methyl-2-aminoisoxazole (0.354 g, 2.0 mmol), NaH (60% oil dispersion) (0.20 g, 5.0mmol) and 5-phenylfuran-2-sulfonyl chloride (0.58 g, 2.4 mmol). Flashchromatography (50% EtOAc/hexane) and recrystallization fromCHCl₃/hexane provided 0.23 g (29% yield) of light yellow crystals (m.p.124-126° C.).

EXAMPLE 72N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide

A. 4-Isopropylphenyl boronic acid

4-Isopropylphenyl boronic acid was prepared in the same manner asdescribed in Example 33B from 1-bromo-4-isopropylbenzene. The boronicacid was isolated as a white powder in 63% yield, m.p. 133-135° C.

B. N-[5-(4-isopropylphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(4-isopropylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in thesame manner as described in Example 33C, from 4-isopropylphenyl boronicacid and N-(5-bromothiophene sulfonyl)-pyrrole. Purification by columnchromatography using 10% ethyl acetate/hexanes gave the pure sulfonamideas an off white colored solid in 84% yield, m.p. 112-114° C.

C. 5-chlorosulfonyl-2-(4-isopropylphenyl)thiophene

5-chlorosulfonyl-2-(4-isopropylphenyl)thiophene was prepared in the samemanner as described in Example 33D. Hydrolysis of 526 mg (1.59 mmol) ofN-[5-(4-isopropylphenylthiophene)-2-sulfonyl]pyrrole with 6N sodiumhydroxide followed by chlorination using phosphorous oxychloride andphosphorous pentachloride gave the crude sulfonyl chloride as dark oil.Flash column chromatography over silica gel using 2% ethylacetate/hexanes yielded 262 mg (55%) of the pure sulfonyl chloride as alight brown oil.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-isopropylphenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of5-chlorosulfonyl-2-(4-isopropylphenyl)thiophene (260 mg, 0.87 mmol) with5-amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) yielded afterflash chromatography using 10% MeOH/CHCl₃ a pale brown solid (265 mg)which was further purified using preparative HPLC to give the puresulfonamide as a light tan colored solid, m.p. 114-116° C.

EXAMPLE 73N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide

A. 1-bromo-4-propylbenzene

A solution of 1-bromopropane (1.32 g, 0.6 mmol) was added dropwise atroom temperature at a rate such that a gentle reflux was maintained to asuspension of magnesium (258 mg, 12 mmol) in dry tetrahydrofuran. Thecloudy suspension was stored at room temperature for an additional 30minutes to produce a gray solution that was then added dropwise over 15minutes to a mixture of 1-iodo-4-bromobenzene (3.0 g, 10.6 mmol) andtetrakis (triphenylphosphine) palladium (O) in 50 mL of dry benzene atroom temperature. The mixture was stirred for 2 hours, diluted with 50mL of water, the organic layer was separated and the aqueous layer wasextracted with ether (2×50 mL). The combined organic extracts was driedand evaporated to yield 1.69 g (80%) of a light brown oil, which wasused in the next step without further purification.

B. 4-propylphenyl boronic acid

To a suspension of magnesium shavings (217 mg, 8.9 mmol) in 3 mL of drytetrahydrofuran under argon, a crystal of iodine along with a solutionof 4-bromopropylbenzene (1.69 g, 8.5 mmol) dissolved in 6 mL oftetrahydrofuran was added at such a rate that a gentle reflux wasmaintained. The solution was refluxed for an additional 0.5 h, cooled toroom temperature and added in portions over 10 min to a solution oftrimethylborate (924 mg, 8.9 mmol) previously dissolved in 4 mL of dryether at −78° C. After 30 minutes, the solution was warmed to roomtemperature; and stirring was continued for 90 min. The reaction wasthen quenched by the addition of 2 mL of a 10% hydrochloric acidsolution. The tetrahydrofuran was removed under reduced pressure and theremaining residue was extracted into diethyl ether (3×25 mL). Thecombined ether extracts was extracted with 1 M NaOH (3×25 mL) and theresulting aqueous layer was acidified to pH 2.0 using 6N HCl, thenreextracted back into diethyl ether (3×25 mL). The combined organiclayers was washed with water (1×25 mL), brine (1×25 mL) and dried overmagnesium sulfate. Evaporation of solvent left a brown solid which wasfiltered through a small plug of silica gel using 10% MeOH/CHCl₃.Evaporation left 448 mg (32%) of a brown solid, m.p. 90-93° C.

C. N-[5-(4-propylphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(4-propylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in thesame manner as described in Example 33C, from 4-propylphenyl boronicacid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by columnchromatography using 10% ethyl acetate/hexanes gave the pure sulfonamideas a white solid in 55% yield, m.p. 106-108° C.

D. 5-chlorosulfonyl-2-(4-propylphenyl)thiophene

5-chlorosulfonyl-2-{4-propylphenyl)thiophene was prepared in the samemanner as described in Example 33D. Hydrolysis of 240 mg (0.73 mmol) ofN-[5-(4-propylphenylthiophene)-2-sulfonyl]pyrrole with 6N NaOH followedby chlorination using phosphorous oxychloride and phosphorouspentachloride gave the crude sulfonyl chloride as a greenish-brown oil.Flash chromatography over silica gel using 2% ethyl acetate/hexanesyielded 83 mg (81%) of the pure sulfonyl chloride as a pale yellow oil.

E.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-propylphenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of5-chlorosulfonyl-2-(4-propylphenyl)thiophene (260 mg, 0.87 mmol) with5-amino-4-bromo-3-methylisoxazole (161 mg, 0.91 mmol) yielded afterflash chromatography using 10% MeOH/CHCl₃ a brown solid (76.1 mg) whichwas further purified using preparative HPLC to give the pure sulfonamideas a tan colored oil.

EXAMPLE 74N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]-thiophene-3-sulfonamide

A. a-(2-benzo[b]thienyl)-3,4,5-trimethoxybenzyl alcohol

a-(2-benzo[b]thienyl)-3,4,5-trimethoxybenzyl alcohol was prepared in thesame manner as described in Example 40A. Reaction of benzo[b]thiophene(7.5 mmoles, 1.0 g), t-BuLi (1.7m, 9.7 mmoles, 5.7 mls) and3,4,5-trimethoxybenzaldehyde (8.9 mmoles, 1.8 g) in THF (20 ml) yielded,after flash chromatography using 50% ethyl acetate/hexanes, 2.4 g (97%)of a yellow-white solid.

B. 2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene

2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene was prepared in the samemanner as described in Example 47B. Reaction ofa-(2-benzo[b]-thienyl)-3,4,5-trimethoxybenzyl alcohol (4.5 mmoles, 1.5g), triethylsilane (5.0 mmoles, 0.80 mls), CH₂Cl₂ (50 ml) and TFA (9.1mmoles, 0.70 mls) yielded, after flash chromatography using 20% ethylacetate/hexanes, 0.77 g (54%) of a white solid.

C. 2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride,

2-(3,4, 5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride, wasprepared in the same manner as described in Example 40B. Reaction ofdimethylformamide (DMF; 4.8 mmoles, 0.40 mls), sulfuryl chloride (4.1mmoles, 0.33 mls) and 2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene (2.4mmoles, 0.75 g) yielded, after flash chromatography using 20% ethylacetate/hexanes, 0.29 g (30%) of a yellow-orange oil.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4,5-trimethoxybenzyl)-benzo[b]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 41. Reaction of4-bromo-3-methyl-5-aminoisoxazole (0.55 mmoles, 97 mg), NaH (1.4 mmoles,55 mg), and 2-(3,4,5-trimethoxylbenzyl)-benzo[b]thiophene-3-sulfonylchloride (0.66 mmoles, 0.27 g) in THF (2 ml) yielded, after flashchromatography using 50% ethyl acetate/hexanes and recrystallizationfrom chloroform and hexanes, 94 mg of a tan solid, m.p. 154-156° C.

EXAMPLE 75 N-(4-bromo-3-methyl-5-isoxazolyl)2-ethyl-5-methylbenzo[b]thiophene-3-sulfonamide

A. 2-ethyl-5-methylbenzo[b]thiophene

2-ethyl-5-methylbenzo[b]thiophene was prepared in the same manner asdescribed in Example 40A. Reaction of 5-methylbenzo[b]thiophene (3.4mmoles, 0.50 g), t-BuLi (1.7 m, 5.1 mmoles, 3.0 ml) and ethyl iodide(6.8 mmoles, 0.54 ml) in THF (10 ml) yielded 0.58 g (97%) of a lightyellow liquid.

B. 2-ethyl-5-methylbenzo[b]thiophene-3-sulfonylchloride

2-ethyl-5-methylbenzo[b]thiophene-3-sulfonylchloride was prepared in thesame manner as described in Example 40B. Reaction of DMF (6.5 mmoles,0.50 ml), sulfurylchloride (5.5 mmoles, 0.44 ml) and2-ethyl-5-methylbenzo[b]thiophene (3.2 mmoles, 0.57 g) yielded, afterflash chromatography, using 2% ethyl acetate/hexanes, 0.58 g (66%) of anorange solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5-methylbenzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-ethyl-5-methylbenzo[b]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 41. Reaction of4-bromo-3-methyl-5-aminoisoxazole (1.0 mmole, 0.18 g), NaH (2.5 mmoles,0.10 g), and 2-ethyl-5-methylbenzo[b]thiophene-3-sulfonylchloride (1.3mmoles, 0.36 g) in THF (6 ml) yielded, after recrystallization fromchloroform and hexanes, 0.25 g (60%) of a light brown crystalline solid,m.p. 176-178° C.

EXAMPLE 76N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 41. Reaction of4-chloro-3-methyl-5-aminoisoxazole (0.61 mmoles, 81 mg), NaH (1.5mmoles), 61 mg), and2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonyl chloride(0.74 mmoles, 0.27 g) in THF (4 ml) yielded, after flash chromatographyusing 50% ethyl acetate/hexanes followed by recrystallization from ethylacetate and hexanes, 0.23 g (81%) of a light brown solid, m.p. 178-181°C.

EXAMPLE 77N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide

A. a-(2-benzo[b]thienyl)-3,4-dimethoxybenzyl alcohol

a-(2-benzo[b]thienyl)-3,4-dimethoxybenzyl alcohol was prepared in thesame manner as described in Example 40A. Reaction of benzo[b]-thiophene(7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 97 mmoles, 5.7 ml) and3,4-dimethoxybenzaldehyde (8.9 mmoles, 1.5 g) in THF (20 ml) yielded,after flash chromatography using 30% ethyl acetate/hexanes, 2.25 g(≈100%) of a white gummy solid.

B. 2-(3,4-dimethoxybenzyl)benzo[b]thiophene

2-(3,4-dimethoxybenzyl)benzo[b]thiophene was prepared in the same manneras described in Example 47B. Reaction ofa-(2-benzo[b]thienyl)-3-4-dimethoxybenzyl alcohol (7.5 mmoles, 2.25 g),triethylsilane (8.2 mmoles, 1.3 ml) and CH₂Cl₂ (20 ml) in TFA (15mmoles, 1.2 mls) yielded, after flash chromatography using 10% ethylacetate/hexanes, 1.77 g (84%) of a colorless oil.

C. 2-(3,4-dimethoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride

2-(3,4-dimethoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride wasprepared in the same manner as described in Example 40B. Reaction of DMF(90 mmoles, 7 ml) and 2-(3,4-dimethoxybenzyl)-benzo[b]thiophene (6.0mmoles, 1.7 g) yielded, after flash chromatography using 15% ethylacetate/hexanes, 1.24 g (54%) of a green oil.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxybenzyl)-benzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-benzyl)-benzo[b]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 41. Reaction of4-bromo-3-methyl-5-aminoisoxazole (1.0 mmoles, 0.18 g), NaH (2.5 mmoles,60 mg), and 2-(3,4-dimethoxybenzyl)benzo[b]thiophene-3-sulfonylchloride(1.2 mmoles, 0.449) in THF (6 ml), after recrystallization fromchloroform and hexanes, yielded 0.42 g (80%) of a brown solid, m.p.151-153° C.

EXAMPLE 78N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-methylenedioxybenzyl)-benzo[b]thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(3,4-methylenedioxybenzyl)benzo[b]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 41. Reaction of3,4-dimethyl-5-aminoisoxazole (1.0 mmoles, 0.11 g), NaH (2.5 mmoles, 60mg) and2-[3,4-(methylenedioxy)benzyl]-benzo[b]thiophene-3-sulfonylchloride (1.1mmoles, 0.40 9) in THF (6 ml) yielded, after flash chromatography using50% ethyl acetate/hexanes followed by recrystallization from chloroformand hexanes, 0.35 g (79%) of a tan solid, m.p. 135-137° C.

EXAMPLE 79N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)benzo[b]-thiophene-3-sulfonamide

A. a-(2-benzo[b]thienyl)-4-methyoxybenzyl alcohol

a-(2-benzo[b]thienyl)-4-methyoxybenzyl alcohol was prepared by themethod of Example 40A with benzo[b]thiophene (7.5 mmoles. 1.0 g), t-BuLi(1.7 m, 10.4 mmoles, 6.1 ml), 4-methoxy-benzaldehyde (8.9 mmoles, 1.1ml) and THF (20 ml). Flash chromatography (20% ethyl acetate/hexanes)provided 1.75 g (87%) of a yellow solid.

B. 2-(4-methyoxybenzyl)-benzo[b]thiophene

2-(4-methyoxybenzyl)-benzo[b]thiophene was prepared by the method ofExample 47B with a-(2-benzo[b]thienyl)-4-methoxybenzyl alcohol (1.9mmoles) 0.50 g), triethysilane (2.0 mmoles, 0.32 mls), CH₂Cl₂ (20 ml)and TFA (3.7 mmoles, 0.30 ml). Recrystallization with hexanes andchloroform provided 0.40 (85%) of a pink solid.

C. 2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride

2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride was prepared bythe method of Example 40B with DMF (3.2 mmoles, 0.24 ml),sulfurylchloride (2.7 mmoles, 0.22 ml) and2-(4-methoyxybenzyl)-benzo[b]thiophene (1.6 mmoles. 0.4 g). Flashchromatography using 2% ethyl acetate/hexanes provided 0.19 g (33%) of alight yellow solid.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 with4-bromo-3-methyl-5-aminoisoxazole (0.48 mmoles, 85 mg), NaH (1.2 mmoles,48 mg), 2-(4-methoxybenzyl)-benzo[b]thiophene-3-sulfonylchloride (0.53mmoles, 0.19 g) and THF (3 ml). Flash chromatography (50% ethylacetate/hexanes) followed by recrystallization from methanol and waterprovided 46 mg (20%) of a white crystalline solid, m.p. 120-122° C.

EXAMPLE 80N-(4-Bromo-3-methyl-5-isoxozolyl)-2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide

A. a-(2-benzo[b]thiophene)-2-methoxybenzyl alcohol

a-(2-Benzo[b]thiophene)-2-methoxybenzyl alcohol was prepared by themethod of Example 47A with benzo[b]thiophene (7.5 mmoles, 1.0 g) t-BuLi(1.7 m, 9.7 mmoles, 5.7 ml), 2-methoxybenzaldehyde (8.9 mmoles, 1.1 ml)and THF (20 ml). Flash chromatography (20% ethyl acetate/hexanes)provided 1.9 g (96%) of a yellow oil.

B. 2-(2-Methoxybenzyl)-benzo[b]thiophene

2-(2-Methoxybenzyl)-benzo[b]thiophene was prepared by the method ofExample 47B a-(2-benzo[b]thiophene)-2-methoxybenzyl alcohol (7.1 mmoles,1.9 g), triethylsilane (7.9 mmoles, 1.3 ml) and CH₂Cl₂ (30 ml) at 0° C.was added TFA (14.3 mmoles, 1.1 ml). Flash chromatography (2% ethylacetate/hexanes) provided 1.31 g (72%) of a yellow solid.

C. 2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl chloride

2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl chloride was preparedby the method of Example 40B with sulfuryl chloride (8.4 mmoles, 0.7ml), DMF (9.8 mmoles, 0.8 ml) and 2-(2-methoxybenzyl)-benzo[b]thiophene(4.9 mmoles, 1.25 g). Flash chromatography (2% ethyl acetate/hexanes)provided 0.94 g (54%) of a yellow solid.

D.N-(4-bromo-3-methyl-5-isoxozolyl)-2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxozolyl)-2-(2-methoxybenzyl)-benzo[b]-thiophene-3-sulfonamidewas prepared by the method of Example 41 with5-amino-4-bromo-3-methylisoxazole (1.0 mmoles, 0.18 g), NaH (2.5 mmoles,100 mg), 2-(2-methoxybenzyl)-benzo[b]thiophene-3-sulfonyl chloride (1.4mmoles, 0.49 g) and THF (7 ml). Flash chromatography (50% ethylacetate/hexanes) followed by recrystallization from chloroform andhexanes provided 0.30 g (61%) of a brown solid, m.p. 80-84° C.

EXAMPLE 81N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonamide

A. a-(2-benzo[b]thienyl)-4-chlorobenzyl alcohol

a-(2-benzo[b]thienyl)-4-chlorobenzyl alcohol was prepared by the methodof Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7m, 9.7 mmoles, 5.7 ml), 4-chlorobenzaldehyde (9.7 mmoles, 1.4 g) and THF(20 ml). The crude material (2.45 g) was taken forward without furtherpurification.

B. 2-(4-chlorobenzyl)benzo[b]thiophene

2-(4-chlorobenzyl)benzo[b]thiophene was prepared by the method ofExample 47B with a-(2-benzo[b]thiophene)-4-chlorobenzyl alcohol (3.9mmoles, 2.45 g), triethylsilane (9.8 mmoles, 1.6 ml), CH₂Cl₂ (40 ml) andTFA (13.4 mmoles, 1.0 ml). Flash chromatography (1% ethylacetate/hexanes) provided 1.3 g (67%—2 steps) of an off-white solid.

C. 2-(4-chlorobenzyl)benzo[b]thiophene-3-sulfonylchloride

2-(4-chlorobenzyl)benzo[b]thiophene-3-sulfonylchloride was prepared bythe method of Example 40B with DMF (70 mmoles, 5.4 ml), sulfurylchloride(2.3 mmoles, 1.9 ml) and 2-(4-chlorobenzyl)-benzo[b]thiophene (4.6mmoles, 1.2 g). Flash chromatography (2% ethyl acetate/hexanes) provided0.51 g (31%) of an orange-yellow oil.

D.N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 with3,4-dimethyl-5-aminoisoxazole (1.2 mmoles, 1.4 g), NaH (3.0 mmoles, 73mg), 2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonylchloride (1.4mmoles, 0.50 g) and THF (8 ml). Flash chromatography (50% ethylacetate/hexanes) followed by recrystallization from methanol and waterprovided 1.04 g (27%) of a yellow solid, m.p. 100-102° C.

EXAMPLE 82N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)benzo[b]thiophene-3-sulfonamide

A. a-(2-benzo[b]thienyl)-4-dimethylaminobenzyl alcohol

a-(2-benzo[b]thienyl)-4-dimethylaminobenzyl alcohol was prepared by themethod of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi(1.7 M, 8.9 mmoles, 5.3 ml), 4-dimethylaminobenzaldehyde (8.9 mmoles,1.3 g) and THF (20 ml). The crude product (2.4 g) was carried forwardwithout further purification.

B. 2-(4-dimethyaminobenzyl)benzo[b]thiophene

2-(4-dimethyaminobenzyl)benzo[b]thiophene was prepared by the method ofExample 47B with a-(2-benzo[b]thienyl)-4-dimethylaminobenzyl alcohol(7.5 mmoles, 2.1 g), triethylsilane (2.8 mmoles, 1.3 ml), CH₂Cl₂ (50 ml)and TFA (11.2 mmoles, 0.9 ml). Flash chromatography (10% ethylacetate/hexanes) provided 1.5 g (73%—for two steps) of a white solid.

C. 2-(4-dimethylaminobenzyl)-benzo[b]thiophene-3-sulfonylchloride

Chlorosulfonic acid (9.4 mmoles, 0.6 ml) was added to2-(4-dimethylaminobenzyl)-benzo[b]thiophene (3.7 mmoles, 1.0 g) inCH₂Cl₂ (100 ml) at −78° C. The solution was stirred 20 min. at −78° C.Phosphorous oxychloride (11.2 mmoles, 1.0 ml) and phosphorouspentachloride (11.2 mmoles, 2.3 g) were added to the reaction mixture.The reaction mixture was warmed to ambient temperature and stirring wascontinued an additional 1.5 hr. followed by dilution with ice (≈200 ml)and extraction with ethyl acetate (200 ml). The organic layer was washedcarefully with sat. NaHCO₃ (3×100 ml), then dried (MgSO₄), filtered andconcentrated. Flash chromatography (5% ethyl acetate/hexanes) provided0.61 g (45%) of a yellow solid.

D.N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)-benzo[b]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)-benzo[b]thiophene-3-sulfonamidewas prepared by the method of Example 41 with4-chloro-3-methyl-5-aminoisoxazole (0.52 mmoles, 69 mg), NaH (1.3mmoles, 31 mg),2-(4-dimethylaminobenzyl)-benzo[b]thiophene-3-sulfonylchloride (0.58mmoles, 0.21 g) and THF (4 ml). Flash chromatography (5%methanol/chloroform) provided 0.16 g (66%) of a yellow gummy solid, m.p.105-1 10° C.

EXAMPLE 83N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylfuran-3-sulfonamide

A. 2,5-dimethyl-furan-3-sulfonylchloride

2,5-dimethyl-furan-3-sulfonylchloride was prepared by the method ofExample 40B with DMF (28 mmoles, 2.2 ml), sulfurylchloride (24 mmoles,1.9 ml) and 2,5-dimethyl-furan (14 mmoles, 1.5 ml). Flash chromatography(5% ethyl acetate/hexanes) provided 0.61 g (22%) of a yellow liquid.

B. N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-furan-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-furan-3-sulfonamide wasprepared by the method of Example 41 with4-bromo-3-methyl-5-amino-isoxazole (2.0 mmoles, 0.35 g), NaH (5.0mmoles, 200 mg), 2,5-dimethyl-furan-3-sulfonylchloride (2.4 mmoles, 0.47g) and THF (9 ml). Flash chromatography (5% methanol/chloroform)followed by recrystallization from chloroform and hexanes provided 0.21g (31%) of a light brown solid, m.p. 85.5-87° C.

EXAMPLE 84N-(4-Bromo-3-methyl-5-isoxazolyl)-2,5-dimethyl-4-phenylthiophene-3-sulfonamide

A. 2,5-dimethyl-3,4-dibromothiophene

NBS (13.2 mmoles, 2.4 g) was added to 2,5-dimethylthiopene (5.3 mmoles,0.59 g) in CHCl₃ (30 ml). The reaction mixture was stirred at ambienttemperature for 1.5 hr., then diluted with ether (50 ml) and washed withwater (3×50 ml). The organic was dried (MgSO₄), filtered andconcentrated. Flash chromatography (hexanes) provided 1.2 g (84%) of awhite solid.

B. 2,5-dimethyl-3-bromo-4-phenylthiophene

Phenyl boronic acid (5.0 mmoles, 0.61 g) was added to2,5-dimethyl-3,4-bromothiophene (4.5 mmoles, 1.2 9), tetrakis(triphenylphosphine) palladium(O) (0.23 mmoles, 0.26 g) and Na₂CO₃ (2 M,26 mmoles, 13 ml) in benzene (20 ml). The biphasic reaction mixture washeated to reflux for 24 hr. then cooled to ambient temperature anddiluted with ether (100 ml) and washed with water (100 ml). The organiclater was dried (MgSO₄), filtered and concentrated. Flash chromatography(hexanes) provided 0.60 g (49%) of a yellow solid.

C. 2,5-dimethyl-4-phenyl-3-chlorosulfonyl-thiophene

t-BuLi (1.7 M, 2.7 mmoles, 1.6 ml) was added to2,5-dimethyl-3-bromo-4-phenyl thiophene (2.2 mmoles, 0.59 g) in THF (8mls.) at −30° C. The solution was stirred 20 min. at −30° C., then theflask was evacuated with sulfur dioxide, and warmed to −20° C. uponwhich NCS (2.2 mmoles, 0.30 g) was added. The reaction mixture waswarmed to ambient temperature for 30 min., then diluted with ethylacetate (50 ml) and washed with water (2×50 ml). The organic layer wasdried (MgSO₄), filtered and concentrated. Flash chromatography (2% ethylacetate/hexanes) provided 0.26 g (41%) of a light yellow solid.

D.N-(4-bromo-3-methyl-5-isoxazole)-2,5-dimethyl-4-phenylthiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazole)-2,5-dimethyl-4-phenylthiophene-3-sulfonamidewas prepared by the method of Example 41 with 4-bromo-3-methyl-5-aminoisoxazole (0.79 mmoles, 0.14 g), NaH (2.0 mmoles, 80 mg),2.5-dimethyl-4-phenylthiophene-3-sulfonylchloride (0.91 mmoles, 0.26 g)and THF (3 ml). Recrystallization twice from chloroform and hexanesprovided 0.15 g (45%) of a white crystalline solid, m.p. 166-168° C.

EXAMPLE 85N-(4-Bromo-3-methyl-5-isoxazolyl)-2-(hydroxymethyl)thiophene-3-sulfonamide

BH₃THF (3.62 ml, 1 M in THF) was added to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (1.0g, 2.72 mmol) in dry THF (15 ml) at room temperature. After stirring atroom temperature for 10 minutes, the mixture was refluxed for 1 hour.The reaction was cooled with an ice-bath and 1N HCl (10 ml) was added.The resulting mixture was concentrated. The aqueous residue was thenpartitioned between 1 N HCl and EtOAc. The organic layer was dried(MgSO₄). The solid was filtered and the filtrate concentrated. Theresidue was treated with MeOH and concentrated again. This process wasrepeated 3 more times to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(hydroxymethyl)thiophene-3-sulfonamide(680 mg, 71% yield) as a yellow, oil.

EXAMPLE 86N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)aminomethyl]-thiophene-3-sulfonamide

BH₃THF (15 ml, 1 M in THF) was added to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-methoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide(Example 22) (1.0 g, 2.12 mmol) in dry THF (15 ml). The mixture wasrefluxed for 8 hours and cooled. THF was evaporated on a rotavap andMeOH was added to the residue. The resulting solution was concentrated.The final residue was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)-aminomethyl]thiophene-3-sulfonamide(113 mg., 12% yield) as a grey powder, m.p. 70-73° C.

EXAMPLE 87N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenylaminocarbonyl]-thiophene-3-sulfonamide

Et₃N (2.27 μl, 16 mmol), ethyl 3-aminobenzoate (836 μl, 5.44 mmol) andphosphonitrilic chloride trimer (1.89 g, 5.44 mmol) were sequentiallyadded to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carbonyl)thiophene-3-sulfonamide(Example 17) (1 g, 2.27 mmol) in dry THF (20 ml). The reaction wasstirred at room temperature for 1 hour and cooled. Water (5 ml) wasadded to quench the reaction. The resulting solution was concentrated ona rotavap. The residue was diluted with EtOAc and washed with 2N HCl(2×150 ml). The organic layer was dried (MgSO₄). The solid was filteredoff and the filtrate was concentrated. The residue was treated with 1 NNaOH (200 ml) and stirred at 0° C. for 15 minutes. The mixture was thenacidified with conc. HCl to pH 1. The resulting yellow precipitate wasfiltered off and recrystallized from CH₃CN/H₂O to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(3-carboxyphenyl)aminocarbonyl]thiophene-3-sulfonamide(153 mg., 11.6%) as a yellowish powder, m.p. 183-185° C.

EXAMPLE 88N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[N-(2-carboxylphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-(2-carboxylphenyl)amino-carbonyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 87, with theexception of using ethyl-2-aminobenzoate instead ofethyl-3-aminobenzoate.

EXAMPLE 89N-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfonamido

Carbonyldiimidazole (485 mg, 2.99 mmol) was added to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide (1g, 2.72 mmol) in THF (10 ml) at room temperature. The mixture wasstirred for 15 minutes. Aqueous NH₃ (5 ml) was then added, and themixture was stirred at room temperature for 30 minutes. The solvent wasevaporated and the residue was partitioned between EtOAc and 1N HCl. Theorganic layer was dried (MgSO₄). The solid was filtered and the filtrateconcentrated. The oily residue was recrystallized from EtOAc to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfonamide(946 mg, 95% yield) as a white solid, m.p. 168-170° C.

EXAMPLE 90N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino-1-naphthyl)-sulfonylaminocarbonyl]thiophene-3-sulfonamide

Dansylchloride (90.2 mg, 0.328 mmol) was added to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-(aminocarbonyl)thiophene-3-sulfonamide(Example 89) (100 mg, 0.273 mmol) and NaH (43.7 mg, 60% dispersion inmineral oil, 1.10 mmol). The reaction was stirred at room temperaturefor 1 hour. Water was added to quench the reaction and THF was strippedoff on a rotavap. The aqueous residue was partitioned between 1N HCl andEtOAc. The organic layer was dried (MgSO₄). The solid was filtered andthe filtrate concentrated. The residue was recrystalized from EtOAc togiveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(5-dimethylamino-1-naphthyl)sulfonylaminocarbonyl]thiophene-3-sulfonamide(55 mg., 34% yield) as a white powder (m.p. 184-186° C.).

EXAMPLE 91N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxyphenyl)amino-carbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxyphenyl)-aminocarbonyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 89 with theexception that 3,4-methylenedioxyaniline was used in place of ammoniumhydroxide.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas purified by HPLC to give 15% yield of the desired product as a darkgrey powder, m.p. 138-140° C.

EXAMPLE 92N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamide

Carbonyldiimidazole (530 mg., 3.26 mmol.) was added to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide(Example 17) (1.0 g, 2.72 mmol) in dry THF (10 ml). The mixture wasstirred at room temperature for 15 minutes. Sesamol (767 mg., 5.44 mmol)and imidazole (185 mg, 2.72 mmol) were added simultaneously. Theresulting mixture was refluxed for 1 hour and allowed to cool to roomtemperature. The solvent was evaporated. The residue was partitionedbetween 1N HCl and EtOAc. The organic layer was dried (MgSO₄). The solidwas filtered and the filtrate concentrated to give a yellow oil whichwas recrystalized from EtOAc/Et₂O/Hexane.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamidewas obtained as a white powder (494 mg, 37% yield), m.p. 174-176° C.

EXAMPLE 93N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzoyl]-thiophene-3-sulfonamide

A.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl)carboxamide]thiophene-3-sulfonamidewas prepared by the same method as described in Example 89 with theexception that N,O-dimethylhydroxylamine was used in place of ammoniumhydroxide. The yield was 90%.

B.N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)-benzoyl]thiophene-3-sulfonamide

Freshly prepared (3,4-methylenedioxy)phenyl magnesium bromide (1.28 g of(3,4-methylenedioxy)bromobenzene and 172 mg Mg turnings) was added to asolution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methoxy-N-methyl)aminocarbonyl]thiophene-3-sulfonamide(A) (652 mg, 1.59 mmol) in THF (10 ml) at room temperature. Theresulting mixture was refluxed for 30 minutes. To workup, the mixturewas allowed to cool to room temperature and was quenched with 1N HCl (10ml). THF was then evaporated. The aqueous residue was partitionedbetween 1N HCl and EtOAc. The organic layer was concentrated and theresidue was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzoyl]thiophene-3-sulfonamide(90 mg, 12% yield) as a dark yellow powder, m.p. 47-49° C.

EXAMPLE 94N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 89 with theexception that 3-aminophenol was used in place of ammonium hydroxide.The product was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-hydroxyphenyl)aminocarbonyl]thiophene-3-sulfonamide(50 mg, 18% yield) as a dull yellow solid, m.p. 42-44° C.

EXAMPLE 95N-(3,4-dimethyl-5-isoxazolyl)-2[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2[3,4-(methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamide wasprepared by the same method as described in Example 92 with theexception thatN-(3,4-dimethyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide was usedinstead ofN-(3-bromo-4-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N-(3,4-dimethyl-5-isoxazolyl)-2[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamidewas purified by HPLC and was obtained as an orange oil (200 mg., 15%yield).

EXAMPLE 96N-(4-Bromo-3-methyl-5-isoxazolyl)-2-{[(3,4-methylenedioxy)benzoyl]-aminocarbonyl}thiophene-3-sulfonamide

Carbonyldiimidazole (213 mg. 1.31 mmol) was added to a solution ofpiperonylic acid (181.5 mg., 1.09 mmol) in dry THF (10 ml). Theresulting mixture was stirred for 15 minutes.N-(4-bromo-3-methyl-5-isoxazolyl)-2-aminocarbonylthiophene-3-sulfonamide(Example 89) (400 mg, 1.09 mmol) and NaH (175 mg, 60% in mineral oil,4.37 mmol) were added sequentially. The mixture was stirred at roomtemperature for 8 hours. Water was added to destroy the excess NaH. Thesolvent was then evaporated and the residue was partitioned between 1NHCl and EtOAc. The organic layer was dried (MgSO₄), the solid filteredand the filtrate concentrated. The residue was recrystalized from EtOActo giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-{[(3,4-methylenedioxy)benzoyl]-aminocarbonyl}thiophene-3-sulfonamide(20 mg, 3.6% yield) as a yellowish powder (m.p. 90-93° C.).

EXAMPLE 97N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 93 with theexception thatN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide wasused instead ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonyl]-thiophene-3-sulfonamidewas recrystalized from EtOAc (49% mg, 20% yield) as a white solid, m.p.189-191° C.

EXAMPLE 98N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamide was prepared by the samemethod as described in Example 93 with the exception thatpiperonylmagnesium chloride was used instead of(3,4-methylenedioxy)-phenylmagnesium bromide and the reaction mixturewas stirred overnight at room temperature instead of refluxing for 30minutes. The crude mixture was purified by HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide(20 mg, 40% yield) as a yellow oil.

EXAMPLE 99N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenoxycarbonylamino]thiophene-3-sulfonamide

Triethylamine (2.28 ml, 16.35 mmol) and diphenylphosphorylazide (773mg., 2.72 mmol) were sequentially added to a solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide(Example 17) (1.0 g, 2.72 mmol) in dry THF (40 ml). The mixture wasstirred for 8 hours. Sesamol (1.54 g, 10.9 mmol) was added and themixture was refluxed for 2 hr. The mixture was allowed to cool to roomtemperature. The solvent was stripped off on a rotavap and the residuewas partitioned between EtOAc and 1N HCl. The organic layer was dried(MgSO₄). The solid was filtered and the filtrate concentrated. Theresidue was purified by HPLC to affordN-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonylamino]thiophene-3-sulfonamide(400 mg, 29% yield) as a beige powder, m.p. 39-43° C.

EXAMPLE 100N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylureido]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylureido]thiophene-3-sulfonamidewas prepared by the same method as described in Example 99 with theexception that 3,4-methylenedioxyaniline was used instead of sesamol.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylureido]thiophene-3-sulfonamide(157 mg, 12% yield) was obtained via HPLC purification as abrownish-greyish powder, m.p. 62-651° C.

EXAMPLE 101N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyloxycarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyloxycarbonyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 97 with theexception that piperonyl alcohol was used instead of sesamol.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-(methylenedioxy)benzyloxycarbonyl]thiophene-3-sulfonamide(210 mg, 15% yield) was obtained via HPLC purification as a yellowishpowder, m.p. 35-38° C.

EXAMPLE 102N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 98 with theexception thatN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide wasused instead ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamide(3 g, 50% yield) was obtained via HPLC purification as a yellow solid,m.p. 35-38° C.

EXAMPLE 103N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenethyloxycarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)-phenethyloxycarbonyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 97 with theexception that (3,4-methylenedioxy)phenethyl alcohol was used instead ofsesamol.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyloxy-carbonyl]thiophene-3-sulfonamide(500 mg, 34% yield) was obtained via HPLC purification as a yellowishoil.

EXAMPLE 104N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4-(3,4-methylenedioxybenzyl)-piperazin-1-yl]carbonyl}thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4-(3,4-methylenedioxybenzyl)piperazin-1-yl]carbonyl}thiophene-3-sulfonamidewas prepared by the same method as described in Example 89 with theexception thatN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide wasused instead ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide, and1-piperonylpiperazine was used instead of ammonium hydroxide.N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4-(3,4-methylenedioxybenzyl)piperazin-1-yl]carbonyl}thiophene-3-sulfonamide(872 mg, 54% yield) was obtained via HPLC purification as a whitepowder, m.p. 221-223° C.

EXAMPLE 105N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide wasprepared by the same method as described in Example 99 except that themixture was refluxed without the addition of sesamol.N-(4-chloro-3-methyl-5-isoxazolyl)-2-aminothiophene-3-sulfonamide (298mg, 31% yield) was obtained via HPLC as a yellow solid, m.p. 39-42° C.

EXAMPLE 106N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-cyano-1-[(3,4-methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamide

Carbonyldiimidazole (603 mg, 3.72 mmol) was added to a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide(Example 17) (1.0 g, 3.1 mmol) in dry THF (40 ml). The mixture (I) wasstirred at room temperature for 15 minutes.

NaH (868 mg, 60% in mineral oil, 21.7 mmol) was added to a solution of(3,4-methylenedioxy)phenylacetonitrile in THF (100 ml). The mixture (II)was refluxed for 30 minutes and then allowed to cool to roomtemperature.

The mixture (I) was then cannulated into mixture (II) while cooled byice-bath and the resulting mixture was allowed to warm to roomtemperature. Water was added to quench excess NaH. THF was then strippedoff on a rotavap. The residue was partitioned between 1N NaOH and Et₂O.The aqueous layer was acidified with concentrated HCl with cooling topH˜1 and extracted with EtOAc. The organic layer was dried (MgSO₄), thesolid filtered and the filtrate concentrated. The residue was purifiedby HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-cyano-1-[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide(277 mg, 19% yield) as a yellowish powder, m.p. 142° C.

EXAMPLE 107N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(dimethylamino)phenoxycarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(dimethylamino)phenoxycarbonyl]thiophene-3-sulfonamidewas prepared by the same method as described in Example 97 with theexception that 3-dimethylaminophenol was used instead of sesamol.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(dimethylamino)phenoxycarbonyl]thiophene-3-sulfonamide(50 mg, 7.3% yield) was obtained via HPLC purification as a dark brownoil.

EXAMPLE 108N-(4-chloro-3-methyl-5-isoxazolyl)-2-(cyclohexyloxycarbonyl)thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(cyclohexyloxycarbonyl)thiophene-3-sulfonamidewas prepared by the same method as described in Example 97 with theexception that cyclohexanol was used instead of sesamol.N-(4-chloro-3-methyl-5-isoxazolyl)-2-(cyclohexyloxycarbonyl)thiophene-3-sulfonamide(29 mg, 5% yield) was obtained via HPLC purification as an off-whitesolid, m.p. 134-137° C.

EXAMPLE 109N-(4-chloro-3-methyl-5-isoxazolyl)-2-[β-hydroxy(3,4-methylenedioxy)phenylethyl]thiophene-3-sulfonamide

LiBH₄ (36.6 mg, 1.68 mmol) was added slowly to a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-methylenedioxy)phenylacetyl]thiophene-3-sulfonamide(Example 102) (74 mg, 0.168 mmol) in the THF (10 ml). The resultingmixture was stirred for 8 hours. Saturated NH₄Cl (aq) was added toquench the excess LiBH₄. The resulting mixture was concentrated on arotavap. The residue was partitioned between EtOAc and 1N HCl. Theorganic layer was dried (MgSO₄), and the solid was filtered.

EXAMPLE 110N,N′-bis{3-[(3,4-dimethyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea

Triethylamine (1.4 ml, 9.93 mmol) and diphenylphosphorylazide (939 mg.,3.31 mmol) were sequentially added to a solution ofN-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide(Example 17) (1.0 g, 3.31 mmol) in THF (50 ml). The resulting mixturewas stirred for minutes at room temperature and then refluxed for 1hour. The mixture was allowed to cool to room temperature. THF wasstripped off by use of a rotavap. The residue was partitioned betweenEtOAc and 1N HCl. The organic layer was dried (MgSO₄), the solidfiltered, and the filtrate concentrated.N,N′-bis{3-[(3,4-dimethyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea(140 mg, 14% yield) was obtained via HPLC purification as a pale powder,m.p. 1 12-1 14° C.

EXAMPLE 111N,N′-bis{3-[(4-bromo-3-methyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea

N,N′-bis{3-[(4-bromo-3-methyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}ureawas prepared by the same method as described in Example 110 with theexception thatN-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxythiophene-3-sulfonamide wasused instead ofN-(3,4-dimethyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N,N′-bis{3-[(4-bromo-3-methyl-5-isoxazolyl)aminosulfonyl]thien-2-yl}urea(80 mg, 15.5% yield) was obtained via HPLC purification as an off-whitesolid, m.p. 127-129° C.

EXAMPLE 112N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide

A. 2-(benzyloxymethyl)thiophene

Sodium hydride (0.41 g, 20 mmol) was added to a solution of 2-thiophenemethanol (2.0 g, 18 mmol) in THF (20 ml) at −40° C. The reaction wasstirred at −40° C. for 25 min., then neat benzylbromide (3.6 g, 20 mmol)was added by syringe. The solution was stirred at −40° C. for 0.5 hr,then at room temperature for 1 hr. The THF was evaporated off and theremaining residue was taken up in ether (˜50 ml). The organic solutionwas washed with water (1×10 ml), brine (1×10 ml) and dried over MgSO₄.Evaporation of solvents left an oil which was purified by columnchromatography using 1% ether-hexanes to give 2.6 g of the thiophene asa pale yellow oil (78% yield).

B. 2-chlorosulfonyl-5-(benzyloxymethyl)thiophene

2-chlorosulfonyl-5-(benzyloxymethyl)thiophene was prepared in the samemanner as described in Example 132A from 2-(benzyloxymethyl)-thiophene(1.0 g, 5.25 mmol). Purification by column chromatography using 2.5%ethyl acetate/hexanes gave 520 mg of the pure thiophene as

a brown oil (32% yield).

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamidewas prepared as described in Example 2 from2-chlorosulfonyl-5-(benzyloxymethyl)thiophene (520 mg, 1.72 mmol) and5-amino-4-bromo-3-methyl isoxazole (319 mg, 1.8 mmol). Purification bycolumn chromatography using 10% MeOH/CHCl₃) gave 238 mg of pureN-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzyloxymethyl)thiophene-2-sulfonamideas brown semisolid (31% yield, m.p. 92° C.).

EXAMPLE 113N-(4—Chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3-sulfonamide

A. 2-Ethylbenzo[b]furan

2-Ethylbenzo[b]furan was prepared by the method of example 40A withbenzo[b]furan (7.3 mmols), 0.86 9) t-BuLi (1.7 m, 9.4 mmols) iodoethane(4 mmols, 0.9 mls) and THF (15 ml). 1.0 g (95%) of a yellow liquid wasisolated.

B. 2-Ethylbenzo[b]furan-3-sulfonyl chloride

2-Ethylbenzo[b]furan-3-sulfonyl chloride was prepared by the method ofExample 82C with 2-ethylbenzo[b]furan (6.9 mmols, 1.0 g), chlorosulfonicacid (8.9 mmols, 0.6 ml) phosphorous oxychloride (21 mmols, 1.9 ml),phosphorous pentachloride (6.9 mmols, 1.4 g) and CH₂Cl₂ (10 ml). Flashchromatography (2% ethyl acetate/hexanes) provided 0.71 g (42%) of anorange solid.

C. N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-ethylbenzo[b]furan-3-sulfonamidecompound was prepared by the method of Example 41 with4-chloro-3-methyl-5-amino-isoxazole (1.0 mmols, 0.13 g), NaH (2.5 mmols,60 mg), 2-ethylbenzo[b]furan-3-sulfonyl chloride (1.2 mmols, 0.28 g) andTHF (7 ml). Flash chromatography (20% ethyl acetate/hexanes) followed byrecrystallization from chloroform and hexane provided 97 mg (28%) of awhite solid, m.p. 132-133.5° C.

EXAMPLE 114N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyl])thiophene-3-sulfonamide

A. N-(2-carbomethoxythiophene-3-sulfonyl)pyrrole

N-(2-carbomethoxythiophene-3-sulfonyl)pyrrole was prepared in the samemanner as described in Example 33A by reacting2-carbomethoxythiophene-3-sulfonyl chloride with pyrrole, 50% yield.

B. N-[(2-hydroxymethyl)thiophene-3-sulfonyl]pyrrole

To a stirred solution of N-(2-carbomethoxythiophene-3-sulfonyl)pyrrole(3.0 g, 11.02 mmole) in a mixture of THF and methanol (3:1 mixture, 40ml) was added sodium borohydride (1.2 g) in six lots over a 30 min.period (exothermic reaction) with constant stirring. The solvent wasremoved under reduced pressure and the residue was dissolved insaturated ammonium chloride solution (50 ml). The crude product wasextracted with ethyl acetate, and the combined organic layers was driedover MgSO₄, and evaporated to give a crude product (2.4 g, 90%), whichwas used directly in the next step.

C. N-[2-(bromomethyl)thiophene-3-sulfonyl]pyrrole

Bromine was added to a stirred mixture of triphenylphosphine (3.1 g, 12mmole) in methylene chloride (50 ml) at 0° C. under nitrogen atmospherewith stirring until the yellow color persisted. A few crystals oftriphenylphosphine were added to consume excess bromine followed bypyridine (1.21 ml), andN-[(2-hydroxymethyl)-thiophene-3-sulfonyl]pyrrole dissolved in methylenechloride (10 ml) was added. The reaction was stirred at 0° C. for 1 hrand concentrated to give a crude product. The crude product was purifiedby flash chromatography on silica gel using 10:1 hexane in ethyl acetateto give N-[2-(bromomethyl)thiophene-3-sulfonyl]pyrrole (2.7 g, 80%yield).

D. N-{2-[(3,4-methylenedioxy)benzyl]thiophene3sulfonyl]}pyrrole

N-{2-[(3,4-methylenedioxy)benzyl]thiophene-3-sulfonyl]}pyrrole wasprepared in the same manner as described in Example 32C usingN-[2-(bromomethyl)thiophene-3-sulfonyl]pyrrole and3,4-methylenedioxyphenylboronic acid, 53% yield.

E. ³-chlorosulfonyl-2-[(3,4-methylenedioxy)benzyl]thiophene

3-chlorosulfonyl-2-(3,4-methylenedioxybenzyl)thiophene was prepared inthe same manner as described in Example 65E fromN-{2-[(3,4-methylenedioxy)benzyl]-3-sulfonyl}pyrrole by basic hydrolysisof the sulfonamide to the sodium salt of sulfonic acid and by conversionof this salt to the corresponding sulfonyl chloride, 54% yield.

F.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxybenzyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyl]-thiophene-3-sulfonamidewas prepared in the same manner as described in Example 2 by reacting5-amino-4-bromo-3-methylisoxazole and3-chlorosulfonyl-2-[(3,4-methylenedioxy)benzyl]thiophene. The crudeproduct was purified by HPLC, 37% yield.

EXAMPLE 115N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamide

A. N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(2-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in thesame manner as described in Example 32C using 2-methoxyphenylboronicacid and N-(5-bromothiophenesulfonyl)pyrrole, 74% yield.

B. 5-chlorosulfonyl-2-(2-methoxyphenyl)thiophene

5-chlorosulfonyl-2-(2-methoxyphenyl)thiophene was prepared in the samemanner as described in Example 65E fromN-[5-(2-methoxyphenyl)-thiophene-2-sulfonyl]pyrrole by hydrolysis of thesulfonamide to the sodium salt of sulfonic acid (83%) followed byconversion of the salt to the corresponding sulfonyl chloride, resultingin a 24% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methoxyphenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 1. Reaction of2-chlorosulfonyl-5-(2-methoxyphenyl)thiophene with5-amino-4-bromo-3-methylisoxazole gaveN-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyoxyphenyl)thiophene-2-sulfonamidein 32% yield, m.p. 114-117° C.

EXAMPLE 116N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide

A. 2-(2-tolyl)thiophene

Sodium carbonate (5 ml., 2M aqueous solution) followed by2-methylphenylboronic acid (0.294 g, 2.4 mmol) were added to a solutionof 2-bromothiophene (0.542 g, 2 mmol) andtetrakis(triphenylphosphine)-palladium(O) (100 mg) in toluene (5 ml) andethanol (5 ml) under nitrogen. The mixture was refluxed for 2 hours,cooled to room temperature and extracted with ethyl acetate (2×50 ml).The combined organic layers was dried over MgSO₄ and evaporated. Theresidue was flash chromatographed on silica gel using hexane as eluentto afford 1.2 g of 2-(2-tolyl)thiophene as a colorless gum.

B. 2-chlorosulfonyl-5-(2-tolyl)thiophene

To the cold (−5 to 0° C.) solution of 2-(2-tolyl)thiophene (0.87 g, 5mmole) was added chlorosulfonic acid (0.33 ml, 5 mmole) over a 15 min.period with constant stirring. After 10 min., phosphorous oxychloride (2ml) and phosphorous pentachloride were added. The reaction mixture wasslowly allowed to attain ambient temperature and stirred for 3 hours.The mixture was then poured onto crushed ice (50 g) and was extractedwith ethyl acetate (2×50 ml). The combined organic layers was dried overMgSO₄ and evaporated. The residue was purified by flash columnchromatography on silica gel using 2% ethyl acetate in hexane to give2-chlorosulfonyl-5-(2-tolyl)thiophene, (1.1 g, 72% yield).

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide wasprepared in the same manner as described in Example 2. Reaction of5-chlorosulfonyl-2-(2-tolyl)thiophene with5-amino-4-bromo-3-methylisoxazole gave the crude product which waspurified by column chromatography giving the pure product (gum). Thisgum was dissolved in 5 ml of NH₄OH, concentrated and dried under highvacuum to get the ammonium salt ofN-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-tolyl)thiophene-2-sulfonamide in67% yield, m.p. 180-184° C. (NH₃ ⁺ salt).

EXAMPLE 117N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)thiophene-2-sulfonamide

A. 2-(3-tolyl)thiophene

2-(3-tolyl)thiophene was prepared in the same manner as described inExample 116A using 2-bromothiophene and 3-methylphenylboronic acid. Thecrude product was purified by flash chromatography on silica gel usinghexane as the eluent (86% yield).

B. 2-chlorosulfonyl-5-(3-tolyl)thiophene

2-chlorosulfonyl-5-(3-tolyl)thiophene was prepared in the same manner asdescribed in Example 116B from 2-(3-tolyl)thiophene, 22% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-tolyl)thiophene-2-sulfonamide wasprepared in the same manner as described in the Example 116C using2-chlorosulfonyl-5-(3-tolyl)thiophene and5-amino-4-bromo-3-methylisoxazole. To obtain the ammonium salt of thefinal product, aqueous NH₄OH was used (31% yield; hygroscopic).

EXAMPLE 118N-(4-Bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide

A. 3-benzylthiophene

3-benzylthiophene was prepared in the same manner as described inExample 32C using 3-thienylboronic acid and benzyl bromide, 74% yield.

B. 2-chlorosulfonyl-3-benzylthiophene

2-chlorosulfonyl-3-benzylthiophene was prepared in the same manner asdescribed in Example 117B using 3-benzylthiophene, 78% yield.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-benzylthiophene-2-sulfonamide wasprepared in the same manner as described in Example 2 by reacting2-chlorosulfonyl-3-benzylthiophene with5-amino-4-bromo-3-methylisoxazole resulting in a 24% yield, m.p.180-183° C.

N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-methylfuranyl)thiophene-2-sulfonamide

A. N-[5-(2-methyl-5-furyl)thiophene-2-sulfonyl]pyrrole

t-BuLi (1.7 m solution in hexane, 7.9 ml, 14.6 mmol) was added dropwiseunder constant stirring under a nitrogen atmosphere to a solution of2-methylfuran (1.0 g, 12 mmol) in THF (20 ml) at −78° C. The solutionwas then warmed to −10° C. and stirring continued for 45 min. Thesolution was then added to a solution of zinc chloride (27 ml of a 0.5 Msolution in THF) at −30° C. and then warmed to room temperature wherestirring continued for 1 hr. resulting in a pale yellow clear solution.The solution was then transferred via a steel canula under nitrogen to asolution of N-(5-bromothiophene-2-sulfonyl)pyrrole (Example 33A, 3.5 g,12 mmol) and tetrakis(triphenylphosphine)-palladium (O) (693 mg, 0.6mmol) in THF (15 ml) at −78° C. The solution was then warmed to roomtemperature and stirred for a period of 2 hours. Purification by columnchromatography using 2% ethyl acetate gave 680 mg ofN-[5-(2-methyl-5-furyl)thiophene-2-sulfonyl]pyrrole as a pale yellowpowder (19% yield).

B. 2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride

2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride was prepared in thesame manner as described in Example 33D fromN-[5-(2-methyl-5-furyl)thiophene-2-sulfonyl]pyrrole (300 mg, 1.02 mmol).Purification by column chromatography using 2% ethyl acetate/hexanesgave 145 mg (53%) of the sulfonyl chloride as a pale yellow solid.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-methyl-5-furyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-(2-methyl-5-furyl)thiophene-5-sulfonyl chloride (55 mg, 0.21 mmol)with 5-amino-4-bromo-3-methylisoxazole (41 mg, 0.21 mmol), afterpurification by column chromatography using 10% MeOH/CHCl₃, gave 45 mgof the pure sulfonamide as a brown semisolid (54% yield, m.p. 123-124°C.).

EXAMPLE 120N-(4-Bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 using5-amino-4-bromo-3-methyl-isoxazole (132.75 mg, 0.75 mmole) and4-(phenethyl)thiophene-2-sulfonyl chloride (Example 119D; 225.62 mg,0.75 mmol). The product was purified by HPLC (5-95% acetonitrile with 0.1% TFA over 30 min.) to giveN-(4-bromo-3-methyl-5-isoxazolyl)-4-(phenethyl)thiophene-2-sulfonamideas a brownish oil 72.3 mg, 32% yield.

EXAMPLE 121N-(3,4-dimethyl-5-isoxazolyl)-2-[(4-methylphenyl)aminocarbonyl]-thiophene-3-sulfonamide

Phosphonitrilic chloride trimer dissolved in THF (5 ml) was added to asuspension ofN-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide (2.0g, 6.6 mmol) (Example 28) in THF (5 ml) and Et₃N at 0° C. The cold bathwas removed and the reaction mixture stirred at room temperature for 2hours. The mixture was diluted with water (150 ml) and acidified to pH 2using concentrated hydrochloric acid. The reaction mixture was thenextracted with methylene chloride (2×100 ml), and the combined organiclayers was washed with 2N hydrochloric acid (3×100 ml), dried overMgSO₄, and concentrated be get crude product. The crude product wasdissolved in ether and allowed to stand at room temperature to give aprecipitate which was filtered and washed with cold ether givingN-(3,4-dimethyl-5-isoxazolyl)-2-[(4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide(1.6 g, 61% yield).

EXAMPLE 122N-(4-Bromo-3-methyl-5-isoxazolyl)-5-[(4-tolyl)aminocarbonyl]thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-[(4-tolyl)aminocarbonyl]-thiophene-2-sulfonamidewas prepared in the same manner as described in Example 24 fromN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-carboxybenzene)thiophene-2-sulfonamide(Example 148), 110 mg, 0.25 mmol) and 4-methylaniline (53 mg, 0.49mmol). Purification by recrystallization from methanol/water gave 91 mgof the pure sulfonamide as a light tan powder (61% yield, m.p. 188° C.).

EXAMPLE 123N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]thiophene-3-sulfonamide

A.N-(4-chloro-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamidewas prepared in the same manner as described in Example 17 usingN-(4-chloro-3-methyl-5-isoxazolyl)-2-(carbomethoxy)thiophene-3-sulfonamide,78% yield.

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]-thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]-thiophene-3-sulfonamidewas prepared in the same manner as described in Example 122 usingN-(4-chloro-3-methyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide.The crude product was dissolved in a small quantity of EtOAc (2 ml) andether (15 ml) was added. The resulting precipitate was filtered andwashed with cold ether (50 ml) givingN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]-thiophene-3-sulfonamidein 53% yield (m.p. 177-179°).

EXAMPLE 124N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(N-methyl)-N-phenylaminocarbonyl]-thiophene-3-sulfonamide

A solution ofN-(4-bromo-3-methyl-5-isoxazolyl)-2-(carboxyl)-thiophene-3-sulfonamide(183.6 mg, 0.5 mmol) in dry THF (1 ml) was added to a solution ofN-methylaniline (0.066 ml, 0.6 mmol) in THF (0.5 ml). Triethylamine(0.63 ml, 4.2 mmol) was added to the mixture and, after 10 min., asolution of phosphonitrilic chloride trimer (210.7 mg, 0.6 mmol) wasadded. The mixture was stirred for 1 hr. at 50° C., cooled, neutralizedwith 10 ml 1N HCl (pH 3) and extracted with ethyl acetate. The extractwas dried over anhydrous magnesium sulfate and the solvent was removedunder reduced pressure to give a crude product which was purified byHPLC (5-95% acetonitrile with 0.1% TFA over 30 min.) resulting inN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(N-methyl)-N-phenylaminocarbonyl]thiophene-3-sulfonamideas a white solid (92.1 mg, 39.4% yield, m.p. 51-55° C.).

EXAMPLE 125N-(4-Bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide

A. 3-bromothiophene-2-sulfonyl chloride

Chlorosulfonic acid (20 ml, 300 mmol) was added to a solution of3-bromothiophene (8.15 g, 50 mmol) in methylene chloride (50 ml) at −78°C. over a 20 min. period. After the completion of addition, the coldbath was removed and stirring continued at ambient temperature for 1 hr.The reaction mixture was carefully added, dropwise, to crushed ice (100g). The mixture was extracted with methylene chloride (2×100 ml). Thecombined organic layers was dried over MgSO₄ and evaporated. The crudeproduct was purified by flash chromatography on silica gel using hexaneas the eluent resulting in 3-bromothiophene-2-sulfonyl chloride (4 g,30% yield) and 4-bromothiophene-2-sulfonyl chloride (200 mg,≦1%).

B. N-(3-bromothiophene-2-sulfonyl)pyrrole

N-(3-bromothiophene-2-sulfonyl)pyrrole was prepared in the same manneras described in Example 33A by reacting3-bromothiophene-2-sulfonylchloride with pyrrole (for 16 hr.).N-(3-bromothiophene-2-sulfonyl)pyrrole was obtained in 54% yield.

C. N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole

N-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}pyrrole wasprepared in the same manner as described in Example 32C using3,4-methylenedioxyphenylboronic acid andN-(3-bromothiophene-2-sulfonyl)pyrrole. The crude product was purifiedby flash column chromatography on silica gel using 2% EtOAc in hexane asthe eluent resulting inN-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl}-pyrrole in a 90%yield.

D. 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene

2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl)]thiophene was preparedin the same manner as described in Example 112B usingN-{[3-(3,4-methylenedioxy)phenyl]thiophene-2-sulfonyl) pyrrole by basichydrolysis of the sulfonamide to the sodium sulfonate (100% yield)followed by conversion of the salt to the corresponding sulfonylchloride resulting in a 34% yield of the final product.

E.N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamidewas prepared in the same manner as described in Example 1 by reaction of2-chlorosulfonyl-3-[3,4-(methylenedioxy)-phenyl]thiophene with5-amino-4-bromo-3-methylisoxazole resulting in a 60% yield, m.p.183-186° C.

EXAMPLE 126N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxy)-phenoxymethyl]thiophene-3-sulfonamide

A. N-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}-pyrrole

Sodium hydride (100 mg, 5 mmole) was added to a stirred solution of3,4-methylenedioxyphenol (0.607 g, 4.5 mmol) in DMF (dry, 5 ml) at 0° C.under a nitrogen atmosphere with stirring. The reaction mixture waspermitted to attain room temp and stirring continued for 1 hr. Thereaction mixture was cooled to 0° C. andN-[(2-bromomethyl)thiophene-3-sulfonyl]pyrrole was added. Stirring wascontinued at ambient temperature for 16 hr. The reaction mixture wasdiluted with water (100 ml), extracted with ethyl acetate (2×50 ml) andwashed with 1N NaOH 2×25 ml) to remove phenol derivative. The mixturewas dried over MgSO₄ and concentrated resulting inN-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}pyrrole,which was recrystallized using hexane/EtOAc (1.0 g, 92% yield).

B.3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]-thiophene

3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]-thiophene was prepared in the same manner as described in Example 64EusingN-{2-[(3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonyl}-pyrrole byconducting a basic hydrolysis (using potassium hydroxide iniso-propanol) to the potassium sulfonate followed by conversion of thesalt to the corresponding sulfonyl chloride in an overall yield of 50%.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxy)phenoxymethyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 1 by reaction of3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophenewith 5-amino-4-bromo-3-methylisoxazole, 47% yield, m.p. 152-154° C.

EXAMPLE 127N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]-thiophene-3-sulfonamide

A. Diethyl 2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}phosphonate

N-[2-bromomethyl)thiophene-3-sulfonyl]pyrrole (0.915 g, 3 mmol) wassuspended in triethylphosphite (5 ml) and was heated to 140° C. for 1hr. with stirring under nitrogen atmosphere. Excess triethylphosphatewas removed under reduced pressure and the residue was dried undervacuum resulting in 0.9 g, 83% yield of diethyl2-{3-[(N-pyrrolyl)sulfonyl]-thienylmethyl}phosphonate.

B.N-{2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}-pyrrole

Sodium hydride (200 mg, 60% dispersion) was added in two lots to thestirred solution of diethyl2-{3-[(N-pyrrolyl)sulfonyl]thienylmethyl}-phosphonate (900 mg, 2.48mmol) in dry THF (10 ml) at 0° C. The mixture was stirred at roomtemperature for 1 hr. then piperonal (600 mg) was added. Stirring wascontinued for 12 hours. The mixture was diluted with water (100 ml) andextracted with methylene chloride (2×50 ml). The combined organic layerswas dried over MgSO₄, evaporated, and the residue was flashchromatographed on silica gel using 0.5% ethyl acetate in hexane to giveN-{2-[trans-(3,4-methylenedioxy)cinnamyl]-thiophene-3-sulfonyl}pyrrole(750 mg, 84% yield).

C. 3-chlorosulfonyl-2[trans-3,4-(methylenedioxy)cinnamyl]thiophene

3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene wasprepared in the same manner as described in Example 64E fromN-{2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole bybasic hydrolysis (using isopropanol and potassium hydroxide) to thecorresponding potassium sulfonate (100%) followed by conversion of thesalt to the corresponding sulfonyl chloride in a 31% overall yield.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[trans-3,4-(methylenedioxy)-cinnamyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 1 by reaction of3-chlorosulfonyl-2-[trans-3,4-(methylenedioxy)cinnamyl]thiophene with5-amino-4-bromo-3-methylisoxazole. The crude product was purified byHPLC resulting in a 33% yield, m.p. 147-149° C.

EXAMPLE 128N-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide

A. N-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole

An ethyl acetate (15 ml) solution ofN-{2[trans-3,4-(methylenedioxy)cinnamyl]thiophene-3-sulfonyl}pyrrole(Example 127B, 0.6 g, 1.67 mmol) was subjected to catalytichydrogenation using 10% Pd—C (100 mg) at 55 psi for 14 hr. The catalystwas filtered and the filtrate concentrated to resulting inN-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole (0.55g, 91% yield).

B. 3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene

3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene was preparedin the same manner as described in the Example 64E usingN-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole byconducting basic hydrolysis (iso-propanol and potassium hydroxide) ofthe sulfonamide to the potassium salt of sulfonic acid (93%) followed byconversion of the salt to the corresponding sulfonyl chloride in a 42%yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 2. By reacting3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene with5-amino-4-bromo-3-methylisoxazole and purifying the crude product byHPLC,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamidewas obtained in a 30% yield, m.p. 180° (dec.).

EXAMPLE 129N-(4-Bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamide

A. 3-phenylthiothiophene-2-sulfonyl chloride

A stirred solution of 3-(phenylthio)thiophene (1.0 g, 5.2 mmol) in 5 mlof dry THF was placed under an argon atmosphere and cooled to −78° C.n-butyl lithium (2.78 ml of 2.3M solution) was added over 20 min. andstirring was continued at this temperature for an additional 20 min.Sulfur dioxide gas was then bubbled in at −78° C. for a period of 30min., resulting in the formation of a yellow precipitate. This wasimmediately followed by dropwise addition of N-chlorosuccinimide (764mg, 5.72 mmol) dissolved in THF. The mixture was warmed to roomtemperature and stirring continued for an additional 1.5 hr. The mixturewas then concentrated and the residue dissolved in ether. The organiclayer was washed with water, brine solution and dried over magnesiumsulfate. Evaporation of solvents left a light brown oil which wassubjected to flash chromatography. Elution with 2% ethylacetate-hexanesgave 840 mg (56%) of a pale yellow solid.

B.N-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-3-(phenylthio)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 using5-amino-4-bromo-3-methylisoxazole (192 mg, 1.1 mmol) and3-phenylthiothiophene-2-sulfonyl chloride (300 mg, 1.0 mmol).Purification by column chromatography using 10% MeOH/CHCl₃ yielded 358mg (83%) of the pure sulfonamide as a brown oil.

EXAMPLE 130 N-(3,4dimethyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfonamide

A. N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide was prepared in thesame manner as described in Example 14 using thiophene-2-sulfonylchloride and 3,4-dimethylaminoisoxazole. Purification by columnchromatography using 3% MeOH/CHCl₃ yielded 48%N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide.

B.N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide

N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 32B usingN-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide andmethoxyethoxymethyl chloride resulting in 34% yield. HPLC analysis ofthe crude oil obtained after workup showed that the oil wasapproximately 96% pure and so was used in the next step without furtherpurification.

C.N-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-trimethylsilyl)thiophene-2-sulfonamide

A stirred solution ofN-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-2-sulfonamide(300 mg, 0.87 mmol) in 5.0 ml of dry THF was placed under an argonatmosphere and cooled to −78° C. Over the course of 20 min, a solutionof t-BuLi in hexanes (461 μl of a 2.25 M solution) was added dropwiseand stirring was continued at this temperature for about 25 min. Thenneat trimethylsilylchloride (135 μl, 1 mmol) was added dropwise and thesolution was stirred at −78° C. for 15 min. then at room temp. for 1.5hr. TLC (1% CHCl₃ in MeOH) showed complete reaction of starting materialat this time thus, the reaction was quenched by addition of 2.0 ml ofwater. After evaporation of solvents the remaining residue was extractedinto ethyl acetate, washed with brine solution and dried over magnesiumsulfate. Purification by column chromatography using 20% ethylacetate/hexanes gave the pure sulfonamide as a clear oil 152% yield).

D.N-(methyoxyethoxymethyl)-N-(3,4-dimethylisoxazolyl)-3-(phenylaminocarbonyl)-5-(trimethylsilyl)thiophene-2-sulfonamide

A stirred solution ofN-(methyoxyethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)-5-trimethylsilyl)thiophene-2-sulfonamide(180 mg, 0.43 mmol) in 4 ml of dry THF was placed under an argonatmosphere and cooled to −78° C. At this temperature a solution oft-BuLi in hexanes (215 μl at a 2.55 M solution) was added dropwise andstirring was continued at −78° C. for 0.5 hr. resulting in a clearyellow solution. Phenylisocyanate (77 μl, 0.65 mmol) was added dropwiseat −78° C. and the solution allowed to reach room temperature. Thesolution was then worked up as above in part C. Purification of thefinal product was achieved by column chromatography using 30% ethylacetate/hexanes to give 108 mg of the sulfonamide a 54% yield.

E. N-(3,4dimethyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfonamide

N-(3,4dimethyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 32D usingN-(methyoxyethoxymethyl)-N-(3,4-dimethylisoxazolyl)-3-(N-phenylcarboxamide-5-trimethylsilyl)thiophene-2-sulfonamide(108 mg, 0.23 mmol). Purification was achieved by recrystallization fromacetonitrile/water to give 62 mg (71% yield) N-(3,4dimethyl-5-isoxazolyl)-3-(phenylaminocarbonyl)thiophene-2-sulfonamide asa brown powder, m.p. 152° C.

EXAMPLE 131N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamide

A. Thiophene-3-sulfonyl chloride

n-BuLi (2.38M, 17 ml) was slowly added to a solution of 3-bromothiophene(6.5 g, 40 mmol) in ether (30 ml) at −78° C. The reaction was stirred at−78° C. for 45 min. SO₂ was bubbled through the mixture for minutes at−78° C. followed by the addition of NCS (6.4 g, 48 mmol) as a suspensionin THF (40 ml). The crude product was purified by column chromatographyusing 5% ethyl acetate/hexanes to give 3.92 g thiophene-3-sulfonylchloride as a pale yellow solid (54% yield).

B. N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared in thesame manner as described in Example 14 using thiophene-3-sulfonylchloride and 3,4-dimethylaminoisoxazole resulting in 66% yield as a palebrown solid.

C.2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide

N,N-diisoproplyethylamine (222 μl, 128 mmol) was added to a solution ofN-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (300 mg, 1.16 mmol)in methylene chloride (5 ml), and the mixture was stirred at roomtemperature for 15 min. The mixture was then cooled to 0° C. and2-(trimethysilyl)ethoxy methyl chloride (SEM chloride) (226 μl, 1.28mmol) was added dropwise via syringe, and the resultant yellow solutionwas stirred at room temperature for 5 hours. Evaporation of solventsleft an oil which was extracted into ethyl acetate, washed with waterand brine solution and dried over magnesium sulfate. Flashchromatography of the residue using 10% ethyl acetate/hexanes yielded321 mg2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamideas a clear colorless oil which solidified into a white solid uponstanding (71% yield).

D.2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamide

n-BuLi (2.39 M, 177 μl) was slowly added to a solution of(2-trimethylsilylethoxymethyl)-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide(156 mg, 0.38 mmol) in THF at −78° C. under nitrogen. The reaction wasstirred at −78° C. for 45 min., then benzaldehyde (45 μl, 0.42 mmol) wasadded in one lot at −78° C. and the solution was allowed to come to roomtemperature. Stirring was continued for 1 hr. Purification was achievedby column chromatography using 10% ethyl acetate/hexanes to give 179 mg2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamideas a yellow viscous oil (90% yield).

E.N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamide

To a solution of2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamide(70 mg, 0-14 mmol) in DMF (2 ml) was added cesium fluoride (26 mg, 0.17mmole) in one portion. The resulting mixture was heated to 100° C. for10 hours. The solvents were removed by evaporation under vacuum and theremaining residue was extracted into ethyl acetate, washed with water,brine, and dried over MgSO₄. The product was then purified bychromatography using 50-70% ethyl acetate/hexanes to give 26.2 mgN-(3,4-dimethyl-5-isoxazolyl)-2-(a-hydroxybenzyl)thiophene-3-sulfonamideas a pale white semisolid (51% yield).

EXAMPLE 132N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide

A. N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole

N-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in thesame manner as described in Example 32C using 4-methyl-phenylboronicacid and N-(5-bromothiophenesulfonyl)pyrrole. Purification by columnchromatography using 2% ethyl acetate/hexanes gaveN-[5-(4-methylphenyl)thiophene-2-sulfonyl]pyrrole as a pale yellow solidin 77% yield.

B. 2-chlorosulfonyl-5-(4-methylphenyl)thiophene

2-chlorosulfonyl-5-(4-methylphenyl)thiophene was prepared in the samemanner as described in Example 33D usingN-[5-(4-methylphenyl)-thiophene-2-sulfonyl]pyrrole. Purification bycolumn chromatography using 2% ethyl acetate/hexanes gave2-chlorosulfonyl-5-(4-methylphenyl)thiophene as a pale yellow powder(61% yield).

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methylphenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-(4-methylphenyl)thiophene (100 mg, 0.37 mmol) with5-amino-4-bromo-3-methylisoxazole (65 mg, 0.37 mmol) yielded, aftercolumn chromatography using 10% MeOH/CHCl₃, 96 mg final product as apale yellow solid, (63% yield, m.p. 175° C.).

EXAMPLE 133N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(phenyl)thiophene-2-sulfonamide

A. N-(pyrrole)-5-(phenyl)thiophene-2-sulfonamide

N-(pyrrole)-5-(phenyl)thiophene-2-sulfonamide was prepared in the samemanner as described in Example 32C using phenyl boronic acid andN-(5-bromothiophenesulfonyl)pyrrole. Purification by columnchromatography using 2% ethyl acetate/hexanes gave the pure sulfonamideas a yellow powder in 67% yield.

B. 2-chlorosulfonyl-5-(phenyl)thiophene

2-chlorosulfonyl-5-(phenyl)thiophene was prepared in the same manner asin Example 33D from N-(pyrrole)-5-(phenyl)thiophene-2-sulfonamide.Purification by column chromatography using 2% ethyl acetate/hexanesgave the pure thiophene in 77% yield as a yellow powder.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenyl)thiophene-2-sulfonamide wasprepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-(phenyl)thiophene (94 mg, 0.36 mmol) with5-amino-4-bromo-3-methyl isoxazole (64 mg, 0.36 mmol) yielded, aftercolumn chromatography using 10% MeOH/CHCl₃, 85 mg ofN-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenyl)thiophene-2-sulfonamide as alight brown solid, (59% yield, m.p. 132° C.).

EXAMPLE 134N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl]thiophene-2-sulfonamide

A. N-{5-[4-(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole

N-{5-[4-(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole wasprepared in the same manner as described in Example 32C using4-trifluoromethylbenzene boronic acid and N-(5-bromothiophenesulfonyl)-pyrrole. Purification by column chromatography using 2% ethylacetate/hexanes gave the pure sulfonamide as a white powder in 75%yield.

B. 2-chlorosulfonyl-5-[4-(trifluoromethyl)phenyl]thiophene

2-chlorosulfonyl-5-[4-(trifluoromethyl)phenyl]thiophene was prepared inthe same manner as Example 33D fromN-{5-[4-(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole.Purification by column chromatography using 2% ethyl acetate/hexanesgave the pure thiophene as a white powder in 41% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl]-thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl]-thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-[4-(trifluoromethyl)-phenyl]thiophene (100 mg, 0.31mmol) with 5-amino-4-bromo-3-methyl isoxazole (54 mg, 0.31 mmol)yielded, after column chromatography, 39 mg ofN-(4-bromo-3-methyl-5-isoxazolyl)-5-[4-(trifluoromethyl)phenyl]-thiophene-2-sulfonamideas a pale yellow powder, (27% yield, m.p. 132° C.).

EXAMPLE 135N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide

A. N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide was prepared inthe same manner as described in Example 14 from5-bromothiophene-2-sulfonyl chloride and 5-amino-3-methyl isoxazole.Purification was achieved by extraction of the crude sulfonamide intoaqueous 2N NaOH, washing of the aqueous layer with ethyl acetate andacidification, using concentrated HCl, to pH˜2. Re-extraction into ethylacetate was followed by washing of the organic material with water,brine and drying over magnesium sulfate. After evaporation of solvents,a brownish solid remained which was sufficiently pure to use in the nextstep.

B. N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide wasprepared in the same manner as described in Example 32C from2-formylbenzeneboronic acid (281 mg, 1.87 mmol) andN-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (550 mg, 1.7mmol). Purification by column chromatography using 15% MeOH/CHCl₃ gave163 mg (28%) of the pure sulfonamide as a brown oil.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide

N-bromosuccinamide (81 mg, 0.45 mmol) was added to a solution ofN-(3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamide (155mg, 0.45 mmol) in CHCl₃ (5 ml). The resulting brownish solution wasstirred at room temperature for 3 hours. The solvent was stripped offand the material extracted into ethyl acetate and washed with brinesolution. Evaporation of solvents gave 85 mg of the product (45% yield).A portion of this was further purified by preparative HPLC.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(2-formylphenyl)thiophene-2-sulfonamidewas isolated as a pale brown oil.

EXAMPLE 136N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide

A. N-(3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide wasprepared in the same manner as described in Example 32C from 3-aminobenzene boronic acid (256 mg, 1.87 mmol) andN-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (55 mg, 1.7mmol). At Purification by column chromatography using 15% MeOH/CHCl₃gave 318 mg (56%) of the product.

B.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 30A (withoutacetic acid) usingN-(3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamideresulting in a 33% yield. Further purification was achieved usingpreparative HPLC giving pureN-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-aminophenyl)thiophene-2-sulfonamideas a clear colorless oil.

EXAMPLE 137N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamide

A. N-[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole

A mixture of N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol),3,3-dimethyl-1-butyne (338 mg, 4.1 mmol), copper iodide (39 mg, 0.21mmol), tetrakistriphenylphosphine palladium [Pd(PPh₃)₄] (118 mg, 0.1mmol) and piperidine (5 ml) was stirred at room temperature for a periodof 24 hours under a nitrogen atmosphere. The mixture was then dilutedwith water (10 ml) and extracted with 3×25 ml portions of ether. Thecombined ether extracts are washed with brine and dried over MgSO₄. Thesolvent was removed under reduced pressure and crude product purified bycolumn chromatography using 2% ethyl acetate/hexanes to give 423 mgN-[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole as a yellowpowder (70% yield).

B. 2-chlorosulfonyl-5-(3,3-dimethylbutyn-1-yl)thiophene

2-chlorosulfonyl-5-(t-butylethynyl)thiophene was prepared in the samemanner as described in Example 33D fromN[5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonyl]pyrrole. Purificationby column chromatography using 2% ethyl acetate/hexanes gave the puresulfonamide in 33% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-(3,3-dimethylbutyn-1-yl)thiophene (120 mg. 0.46 mmol)with 5-amino-4-bromo-3-methylisoxazole (85 mg, 0.48 mmol) yielded, aftercolumn chromatography using 10% MeOH/CHCl₃, 116 mgN-(4-bromo-3-methyl-5-isoxazolyl)-5-(3,3-dimethylbutyn-1-yl)thiophene-2-sulfonamideas a viscous clear oil (63%).

EXAMPLE 138N-(4-Bromo-3-methyl-5-isoxazolyl)-5-[3,5-bis(trifluoromethyl)phenyl]-thiophene-2-sulfonamide

A. N-{5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole

N-{5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole wasprepared in the same manner as described in Example 32C from3,5-bis(trifluoromethyl)benzeneboronic acid (619 mg, 2.26 mmol) andN-[5-bromothiophene-2-sulfonyl]pyrrole (60 mg, 2.05 mmol). Purificationby column chromatography using 2% ethyl acetate/hexanes gave the puresulfonamide as a white solid in 93% yield.

B. 2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene

2-chlorosulfonyl-5-[3, 5-bis(trifluoromethyl)phenyl]thiophene wasprepared in the same manner as described in Example 33D fromN-{5-[3,5-bis(trifluoromethyl)phenyl]thiophene-2-sulfonyl}pyrrole.Purification by column chromatography using 2% ethyl acetate/hexanesgave the pure thiophene in 73% yield as a brownish clear oil.

C. N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide was prepared in thesame manner as in Example 2. Reaction of2-chlorosulfonyl-5-[3,5-bis(trifluoromethyl)phenyl]thiophene (250 mg,0.63 mmol) with 5-amino-4-bromo-3-methylisoxazole (118 mg, 0.67 mmol)yielded, after column chromatography using 5% MeOH/CHCl₃, 115.2 mgN-(4-bromo-3-methyl-5-isoxazolyl)-5-[3,5bis(trifluoromethyl)phenyl]thiophene-2-sulfonamide as a white powder(34% yield). A portion of this sample was further purified bypreparative HPLC, m.p. 140° C.

EXAMPLE 139N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamide

A. 2-methylthiophene-5-boronic acid

n-BuLi (2.38 M, 16 ml) was slowly added to a solution of 2-methylthiophene (3.0 g, 31 mmol) in THF (20 ml) at −78° C. The solution waskept at −78° C. for 10 min. then warmed to 0° C. for an additional 0.5hr. The solution was then transferred by steel canula under nitrogeninto a vessel containing triisopropylborate (6.3 g, 33 mmol) in ether(15 ml) at −78° C. The resulting milky white solution was stirred at−78° C. for 20 min. then at room temperature for 2 hours. The reactionwas quenched by the addition of 10% aqueous HCl (5.0 ml) and thesolution was extracted into ether. The combined ether extracts wereextracted with 10M NaOH (2×30 ml), the aqueous extracts were acidifiedwith dilute HCl to pH 2 and extracted into ether (3×25 ml). The combinedether extracts were washed once with water (10 ml), once with brine (10ml) and dried and evaporated to give 3.91 g 2-methylthiophene-5-boronicacid as a light brown solid. This was used in the next step with nofurther purification.

B. N-[5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrole

N-[5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was prepared inthe same manner as described in Example 32C from2-methylthiophene-5-boronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Purification by column chromatography using 2% ether/hexanesgave the pure sulfonamide in 72% yield as a white solid.

C. 2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene

2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene was prepared in thesame manner as described in Example 33D fromN-[5-(5-methyl-2-thienyl)thiophene-2-sulfonyl]pyrrole (570 mg, 1.84mmol). Purification by column chromatography using 2% ethylacetate/hexanes gave 258 mg (50%) of the sulfonyl chloride as a lightgreen solid.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-methyl-2-thienyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-(5-methyl-2-thienyl)thiophene (200 mg, 0.72 mmol)with 5-amino-4-bromo-3-methylisoxazole (127 mg, 0.72 mmol) yielded 273mg (90%) of the crude sulfonamide. After passing through a small plug ofsilica gel, a portion of the product was further purified by preparativeHPLC to give the pure sulfonamide as a white powder, m.p. 161-162° C.

EXAMPLE 140N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide

A. 2-ethylthiophene-5-boronic acid

2-ethylthiophene-5-boronic acid was prepared in the same manner asdescribed in Example 139A from 2-ethylthiophene (2.0 g, 18 mmol).Evaporation of solvents after workup gave 2.16 g (78%) of2-ethylthiophene-5-boronic acid as a white sold which was used on thenext step with no further purification.

B. N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl]pyrrole

N-[5-(5-ethyl-2-thienyl)thiophene-2-sulfonyl]pyrrole was prepared in thesame manner as described in Example 32C from 2-ethylthiophene-5-boronicacid (411 mg, 2.64 mmol) and N-(5-bromothiophene-2-sulfonyl)-pyrrole(700 mg, 2.39 mmol). Purification by column chromatography using 2%ethyl acetate/hexanes gave 630 mg of the pure product as a dark brownsolid (90% yield).

C. 2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene

2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene was prepared in the samemanner as described in Example 33D fromN-(pyrrole)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide (630 mg, 2.16mmol). Purification by column chromatography using 1% ethylacetate/hexanes gave 400.3 mg of the pure sulfonyl chloride as a brightyellow solid (57% yield).

D.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (200 mg, 0.68 mmol) with5-amino-4-bromo-3-methyl isoxazole (121 mg, 0.68 mmol) yielded 174 mgN-(4-bromo-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)-thiophene-2-sulfonamide(59% yield). After passing through a small plug of silica gel withelution using 10% MeOH/CHCl₃, a small fraction of the product wasfurther purified using preparative HPLC to give the sulfonamide as alight tan colored powder, m.p. 126° C.

EXAMPLE 141N-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-5-(5-ethyl-2-thienyl)thiophene-2-sulfonamidewas prepared in the same manner as in Example 2. Reaction of2-chlorosulfonyl-5-(5-ethyl-2-thienyl)thiophene (Example 140C, 200 mg,0.68 mmol) with 5-amino-4-chloro-3-methylisoxazole (91 mg, 0.68 mmol)yielded 188 mg of the final product (71% yield). A small portion of theproduct was further purified by preparative HPLC to give the puresulfonamide as a tan colored solid.

EXAMPLE 142N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamide

A. Benzo[b]thiophene-2-boronic acid

Benzo[b]thiophene-2-boronic acid was prepared in the same manner asdescribed in Example 140A from benzo[b]thiophene except that t-BuLi wasused as the base in place of n-BuLi resulting in a tan solid in 78%yield.

B. N-[5-(benzo[b]thien-2-yl)thiophene-2-sulfonyl]pyrrole

N-[5-(benzo[b]thien-2-yl)thiophene-2-sulfonyl]pyrrole was prepared inthe same manner as described in Example 32C frombenzo[b]-thiophene-2-boronic acid (426 mg, 2.39 mmol) andN-(5-bromothiophene-2-sulfonyl)pyrrole (700 mg, 2.39 mmol). Purificationby column chromatography using 2% ethyl acetate/hexanes gave the puresulfonamide in 68% yield as a brownish-red solid.

C. 2-chlorosulfonyl-5-(benzo[b]thien-2-yl)thiophene

2-chlorosulfonyl-5-(benzo[b]thien-2-yl)thiophene was prepared in thesame manner as in Example 33D fromN-[5-(benzo[b]thien-2-yl)thiophene-2-sulfonyl]pyrrole (520 mg, 1.5mmol). Purification by column chromatography using 2% ethylacetate/hexanes gave 153 mg (32% yield) of the pure sulfonyl chloride asa white solid.

D.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamidewas prepared in the same manner as in Example 2. Reaction of2-chlorosulfonyl-5-(benzo[b]thien-2-yl)thiophene (150 mg, 0.48 mmol)with 5-amino-4-bromo-3-methyl isoxazole (84 mg, 0.48 mmol) resulted in97 mg of pureN-(4-bromo-3-methyl-5-isoxazolyl)-5-(benzo[b]thien-2-yl)thiophene-2-sulfonamideas a light tan powder, (45% yield, m.p. 164° C.).

EXAMPLE 143N-(Bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide

A. N-[5-(1-pentynyl)thiophene-2-sulfonyl)pyrrole

N-[5-(1-pentynyl)thiophene-2-sulfonyl)pyrrole was prepared as in Example138A from N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05 mmol) and1-pentynel (280 mg, 4.1 mmol). Purification by column chromatographyusing 2% ethyl acetate/hexanes gave 424 mg of the pure sulfonamide as abrown oil (74% yield).

B. 2-chlorosulfonyl-5-(1-pentynyl)thiophene

2-chlorosulfonyl-5-(1-pentynyl)thiophene was prepared in the same manneras described in Example 33D fromN-[5-(1-pentynyl)thiophene-2-sulfonyl]pyrrole (420 mg, 1.5 mmol).Purification by column chromatography using 1% ethyl acetate/hexanesgave 55 mg of the pure thiophene as a brown oil (15% yield).

C. N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide

N-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-(1-pentynyl)thiophene (55 mg. 0.22 mmol) with5-amino-4-bromo-3-methylisoxazole (43 mg, 0.22 mmol) yielded 75 mg ofN-(bromo-3-methyl-5-isoxazolyl)-5-(1-pentynyl)thiophene-2-sulfonamide(87% yield). A portion of the product was further purified bypreparative HPLC to give the pure sulfonamide as a light brown oil.

EXAMPLE 144N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)thiophene-2-sulfonamide

A. N-[5-(1-naphthyl)thiophene-2-sulfonyl]pyrrole

N-[5-(1-naphthyl)thiophene-2-sulfonyl]pyrrole was prepared in the samemanner as described in Example 32C from 1-naphthaleneboronic acid (353mg, 2.05 mmol) and N-(5-bromothiophene-2-sulfonyl)pyrrole (600 mg, 2.05mmol). Purification by column chromatography using 2% ethylacetate/hexanes gave the pure sulfonamide in 87% yield as a pale yellowclear oil.

B. 2-chlorosulfonyl-5-(1-naphthyl)thiophene

2-chlorosulfonyl-5-(1-naphthyl)thiophene was prepared as described inExample 33D from

N-[5-(1-naphthyl)thiophene-2-sulfonyl]pyrrole (604 mg, 1.28 mmol).Purification by column chromatography using 2% ethyl acetate/hexanesgave 376 mg of the pure thiophene in 68% yield.

C. N-14-bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)thiophene-sulfonamideN-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)thiophene-sulfonamidewas prepared in the same manner as described in Example 2. Reaction of2-chlorosulfonyl-5-(1-naphthyl)thiophene (200 mg, 0.65 mmol) with5-amino-4-bromo-3-methylisoxazole (0.65 mmol), after purification bycolumn chromatography using 1% MeOH/CHCl₃, gave 65.3 mg of pureN-(4-bromo-3-methyl-5-isoxazolyl)-5-(1-naphthyl)thiophene-sulfonamide asa brown solid, (22% yield, m.p. 118° C.).

EXAMPLE 145N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide

A. N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide

N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide asprepared in the same manner as described in Example 32C from3-nitrobenzene boronic acid (362 mg, 2.17 mmol) andN-(3-methyl-5-isoxazolyl)-5-bromothiophene-2-sulfonamide (700 mg, 2.17mmol). Purification by column chromatography using 10% MeOH/CHCl₃ gave166 mg of the pure sulfonamide (21% yield).

B.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamidewas prepared in the same manner as described in Example 136C. Reactionof N-(3-methyl-5-isoxazolyl)-5-(3-nitrophenyl)thiophene-2-sulfonamide(328 g, 0.90 mmol) with N-bromosuccinamide (160 mg, 0.90 mmol) gave thefinal product. A fraction of this material was further purified bypreparative HPLC to give the pure sulfonamide as a brown solid, m.p.132° C.

EXAMPLE 146N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-methyoxycarbonylphenyl)thiophene-2-sulfonamide

A. 2-(4-methoxycarbonylphenyl)thiophene

2-(4-methoxycarbonylphenyl)thiophene was prepared in the same manner asdescribed in Example 32C from thiophene-2-boronic acid (1.0 g, 7.81mmol) and methyl-4-bromobenzoate (1.68 g, 7.81 mmol). Purification bycolumn chromatography using 2% ethyl acetate/hexanes gave 1.1 g of2-(4-methoxycarbonylphenyl)thiophene as a white solid (65% yield).

B. 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thiophene

Chlorosulfonic acid (1.06 g, 9.16 mmol) was slowly added to a solutionof 2-(4-methoxycarbonylphenyl)thiophene (500 mg, 2.29 mmol) in CH₂Cl₂(10 ml) at −78° C. The resulting solution was stirred at −78° C. for 1hr. by which time the sulfonic acid had completely formed as judged byTLC using 10% ethyl acetate/hexanes. Phosphorous oxychloride (2 ml) wasthen added at −78° C. followed immediately by addition of phosphorouspentachloride (954 mg, 4.58 mmol). The resulting solution was stirred at−78° C. for 0.5 hr. and then at room temperature for 25 min. Thesolution was then carefully poured onto crushed ice (100 g) andextracted into diethyl ether (100 ml). The combined organic layers waswashed with brine (1×25 ml) and dried over MgSO₄. After filtration,removal of solvents left a light greenish solid which was furtherpurified by column chromatography using 2% ethyl acetate/hexanes to give620 mg of pure 2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thiophene asa pale yellow solid (85% yield).

C.N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)-thiophene-2-sulfonamidewas prepared in the same manner as described in Example 2 from2-chlorosulfonyl-5-(4-methoxycarbonylphenyl)thiophene (646 mg, 2.04mmol) and 5-amino-4-bromo-3-methylisoxazole (361 mg, 2.04 mmol).Purification by column chromatography using 10% MeOH/CHCl₃ gave 384 mgofN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-methoxycarbonylphenyl)thiophene-2-sulfonamideas a brown oil (41% yield).

EXAMPLE 147N-(4-Bromo-3-methyl-5-isoxazolyl)-5-(4-carboxyphenyl)thiophene-2-sulfonamide

Lithium hydroxide (13.3 mg, 0.32 mmol) in methanol (2 ml) was added to asolution ofN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-ethoxycarbonylphenyl)thiophene-2-sulfonamide(Example 146C, 121 mg, 0.27 mmol) previously dissolved in methanol (5ml). The solution was stirred at room temperature for a period of 18hours. The methanol was removed in vacuo and the remaining residuedissolved in water. 4N HCl was added until pH 2.0 was reached, and thenthe aqueous solution was extracted with ethyl acetate (3×25 ml). Thecombined organic layers was washed with water (1×10 ml), brine (1×10 ml)and dried over MgSO₄. Evaporation left 50 mg (43% yield) of a paleyellow residue which was further purified by preparative HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-5-(4-carboxyphenyl)thiophene-2-sulfonamideas a white solid, m.p. 219-228° C.

EXAMPLE 148N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)-phenyl]aminocarbonyl}thiophene-3-sulfonamide

Carbonyldiimidazole (553 mg, 3.41 mmol) was added to a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide(1.0 g, 3.1 mmol) in dry DMF (10 ml). The mixture was stirred at roomtemperature for 15 minutes to give mixture (I).

NaH (60% dispersion in mineral oil, 521 mg, 13.02 mmol) was added to asolution of 2′-amino-4′,5′-(methylenedioxy)acetophenone (1.13 g, 6.2mmol) in dry DMF (10 ml) at 0° C. The mixture was stirred at 0° C for 15minutes to give mixture (II). Mixture (I) was slowly cannulated intomixture (II) at 0° C. The resulting mixture was stirred at 0° C for 4hours. The reaction mixture was poured into 2 N HCl (aq., 200 ml) andthe resulting precipitate was filtered. The solid was washed with water(2×10 ml) and ethyl ether (2×10 ml) to giveN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide(730 mg, 49% yield) as a dull yellow powder, m.p. 191-193° C.

EXAMPLE 149N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamideandN-(4-chloro-3-methyl-5-isoxazolyl)2-{{2-[(4,5-dimethoxy-2-methoxycarbonyl)phenylaminocarbonyl]-4,5-dimethoxy}phenylaminocarbonyl}thiophene-3-sulfonamide

The title compounds were prepared by the method set forth forN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]-aminocarbonyl}thiophene-3-sulfonamide(EXAMPLE 148) except that methyl-2-amino-4,5-dimethoxybenzoate was usedinstead of 2′-amino-4′,5′-(methylenedioxy)acetophenone. The crudeproduct was purified via HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamideas a yellow powder (13% yield, m.p. 167-168° C.) andN-(4-chloro-3-methyl-5-isoxazolyl)2-{[4,5-dimethoxy-2,4,5-dimethoxy-2-methoxycarbonyl)-phenyl]phenylaminocarbonyl}thiophene-3-sulfonamideas a dull yellow solid (1% yield, m.p. 228-230° C.).

EXAMPLE 150N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamide

Carbonyldiimidazole (553 mg, 3.4 lmmol) was added to a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxyl-thiophene-3-sulfonamide(10 g, 3.1 mmol) in dry DMF (1.0 ml). The mixture was stirred at roomtemperature for 15 minutes before the sequential addition of2-amino-5-methyl-1,3,4-thiadiazole (736 mg, 6.2 mmol) and pyridine (10ml). The resulting mixture was stirred at room temperature overnight. Towork up, the reaction mixture was poured into 1 N HCl (150 ml) andextracted with EtOAc. The organic layer was dried (MgSO₄), the solid wasfiltered and the filtrate was concentrated. The residue was purified viaHPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamideas a white powder (15% yield, m.p. 192-194° C.).

EXAMPLE 151N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxyl-4,5-(dimethoxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide

NaOH (1.5 N, 250 ml) was added toN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamide(EXAMPLE 149); 410 mg). The resulting suspension was stirred at roomtemperature overnight to give a clear solution. The mixture wasacidified using concentrated HCl with cooling. The resulting precipitatewas filtered, washed with water (3×50 ml) and dried on a lyophilyzer togiveN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxyl-4,5-(dimethoxy)phenyl]aminocarbonyl}thiophene-3-sulfonamideas a yellow powder (87% yield, m.p. 192-195° C.).

EXAMPLE 152N-(3,4-dimethyl-5-isoxazolyl)-2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamidewas prepared by the method set forth forN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide(EXAMPLE 148) except thatN-(3,4-dimethyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide was usedinstead ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.N-(3,4-dimethyl-5-isoxazolyl)-2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamidewas obtained as a yellow powder (8% yield, m.p. 228-231° C.).

EXAMPLE 153N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)-aminocarbonyl]thiophene-3-sulfonamidewas prepared by the method set forth forN-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methyl-1,3,4-thiadiazol-5-yl)aminocarbonyl]thiophene-3-sulfonamide(EXAMPLE 150), except that 4-methoxy-2-methylaniline was used instead of2-amino-5-methyl-1,3,4-thiadiazole and that pyridine was not used. Thetitle compound was obtained via HPLC purification as a dull yellowpowder (66% yield, m.p. 58-62° C.).

EXAMPLE 154N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared by the method set forth forN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide(EXAMPLE 148) except that 2-amino-4,5-dimethoxybenzonitrile was used instead of 2′-amino-4′,5′-(methylenedioxy)acetophenone.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[{2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]-thiophene-3-sulfonamidewas obtained via HPLC purification as a light brown powder (36% yield,m.p. 53-56° C.).

EXAMPLE 155N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared by the method set forth forN-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-methoxy-2-methylphenyl)-aminocarbonyl]thiophene-3-sulfonamide(EXAMPLE 153), except that 2,4-dimethoxyaniline was used in stead of4-methoxy-2-methylaniline.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxyphenyl)aminocarbonyl]-thiophene-3-sulfonamidewas obtained via recrystalization (CH3CN/H2O) as yellow crystals (16%yield, m.p. 162-164° C.).

EXAMPLE 156N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamidewas prepared by the method set forth forN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)-phenyl]aminocarbonyl}thiophene-3-sulfonamide(EXAMPLE 148), except that 2-amino-5-picoline was used in stead of2′-amino-4′,5′-(methylenedioxy)acetophenone,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methyl-6-pyridyl)aminocarbonyl]thiophene-3-sulfonamidewas obtained, via HPLC purification of the crude reaction mixture, as abright yellow powder (17% yield, m.p. 158-160° C.).

EXAMPLE 157

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamidewas prepared in the same manner as described in Example 93B by reacting4-methylbenzylmagnesium chloride withN-(4-bromo-3-methyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)]thiophene-3-sulfonamidein THF (see Example 93A) at −78° C. to room temperature, resulting in78% yield. m.p. 146-150° C. 8

EXAMPLE 158 N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)]thiophene-3-sulfonamide

A. N-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole

N-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole was prepared in the samemanner as described in example 127B usingdiethyl{3-[(N-pyrrolyl)sulfonyl]thien-2-[yl]methylphosphonate and4-methylbenzaldehyde in 30% yield.

B. 2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride

2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride was prepared inthe same manner as described in Example 64E fromN-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole by basic hydrolysis(using ethanol and sodium hydroxide) to the corresponding sodiumsulfonate followed by conversion to the corresponding sulfonyl chloridein 13% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamidewas prepared in the same manner as described in Example 2 by reaction of2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride with5-amino-4-bromo-3-methylisoxazole. The crude product was purified byHPLC followed by crystallization resulting in a 34% yield, m.p. 101-105°C.

EXAMPLE 159N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide

A. N-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole

N-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole was prepared asdescribed in Example 128A by the catalytic hydrogenation ofN-[2-(4-methyl-trans-styryl)-3-sulfonyl}pyrrole in 80% yield.

B. 2-[(4-methyl)phenethyl]thiophene-3-sulfonylchloride

2-[(4-methyl)phenethyl]thiophene-3-sulfonylchloride was prepared, asdescribed in Example 64E, usingN-{2-[(4-methyl)phenethyl]thiophene-3-sulfonyl}pyrrole by basichydrolysis (KOH/ethanol) of the sulfonamide to this potassium saltfollowed by conversion of salt to the corresponding sulfonyl chloride in51% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamidewas prepared, as described in Example 2, using2-[(4-methyl)phenethyl]thiophene-3-sulfonylchloride and5-amino-4-bromo-3-methylisoxazole in 52% yield.

EXAMPLE 160N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide

A. N-{2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl}pyrrole

N-{2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl}pyrrole was prepared,as described in Example 126A, by reacting

N-[2-bromomethyl)thiophene-3-sulfonyl]pyrrole with 4-methylphenol, in81% yield.

B. 2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride

2-[(4-methylphenoxy)methyl]thiophene-3-sulfonyl chloride was prepared,as described in Example 64E, usingN-{2-[(4-methylphenoxymethyl]thiophene-3-sulfonyl}pyrrole by basichydrolysis (NaOH/EtOH) followed by conversion to the correspondingsulfonyl chloride, in 46% yield.

C.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]-thiophene-3-sulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]-thiophene-3-sulfonamidewas prepared, as described in Example 2, by reacting3-chlorosulfonyl-2-[(4-methylphenoxy)methyl]thiophene with5-amino-4-bromo-3-methylisoxazole, resulting in a 64% yield, m.p.128-130° C.

EXAMPLE 161N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetyl)thiophene-3-sulfonamide

A.N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)thiophene-3-sulfonamidewas prepared, as described in Example 93A, by reactingN-(3,4-dimethyl-5-isoxazolyl)-2-(carboxyl)thiophene-3-sulfonamide withN-O-dimethylhydroxylamine hydrochloride using triethylamine as base andcarbonyldiimidazole,resulting in a 23% yield. Crude product purified bycolumn chromatography using 1:1 hexanes/EtOAc as the eluent.

B.N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetyl)thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetyl)thiophene-3-sulfonamidewas prepared, as described in Example 93B, by reactingN-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)]thiophene-3-sulfonamidewith 4-tolylbenzylmagnesium chloride, resulting in a 65% yield, m.p.95-100° C.

EXAMPLE 162N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylacetyl]-thiophene-3-sulfonamidewas prepared, as described in Example 93B, by reactingN-(3,4-dimethyl-5-isoxazolyl)-2-[N-methoxy(methylaminocarbonyl)]thiophene-3-sulfonamidewith 3,4-methylenedioxy)phenylmagnesium chloride, resulting in a 65%yield, m.p. 95-100° C.

EXAMPLE 163N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-cyano-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-cyano-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamidewas prepared as described in EXAMPLE 148, except that2′-amino-4′,5′-(methylene-dioxy)benzonitrile was used instead of2′-amino-4′,5′-(methylenedioxy)acetophenone. It was obtained via HPLCpurification as a yellowish solid in 40% yield, m.p. 167-168° C.

EXAMPLE 164N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide

A. Methyl 3-amino-2,4,6-trimethylbenzoate

Methyl 3-amino-2,4,6-trimethylbenzoate was synthesized in the samemanner as (3,4-methylenedioxy)-6-methylaniline (see Example 177, below).

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamideN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 94 except that DMF wasused instead of THF and the reaction was heated at 80° C. for 5 hours.The crude product was purified via preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methoxycarbonyl-2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamideas an off-white powder (48 mg, 1% yield, m.p. 66-70° C.).

EXAMPLE 165N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 102 using2,4,6-trimethylbenzyl chloride andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (31% yield, m.p. 42-46° C.).

EXAMPLE 166N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 94. The crude product waspurified via preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethyl)phenylaminocarbonyl-3-thiophenesulfonamideas a yellowish-brownish powder (410 mg, 30% yield, m.p. 45-48° C.).

EXAMPLE 167N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized by the same method as described for Example 102 using2,4-dimethylbenzyl chloride andN-(3,4-dimethyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) and further by prepareative HPLC to giveN-(3,4-dimethyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamideas a semi-solid (34% yield).

EXAMPLE 168N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 102 using2,4-dimethylbenzyl chloride andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (52% yield, m.p. 48-54° C.).

EXAMPLE 169N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 102 using2,4-dimethylbenzyl chloride andN-(4-bromo-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 1%methanol in CH₂Cl₂) and further by preparative HPLC to giveN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (28% yield, m.p. 58-63° C.).

EXAMPLE 170N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 102 using3,5-dimethylbenzyl bromide andN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 2%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (57% yield, m.p. 45-50° C.).

EXAMPLE 171N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 102 using2,5-dimethylbenzyl chloride andN-(4-chloro-3-methyl-5-isoxazolyl)-2-JN-methyl-N′-methoxy)aminocarbonyl-3-thiophenesulfonamide.The crude product was purified by flash column chromatography (eluent 2%methanol in CH₂Cl₂) to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,5-dimethyl)phenylacetyl-3-thiophenesulfonamideas a solid (33% yield, m.p. 72-76° C.).

EXAMPLE 172N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide

A. 2-(3,4-methylenedioxy)phenyl-1-ethanol

To a solution of 2-(3,4-methylenedioxy)phenylacetic acid (5 g, 25.75mmol) in anhydrous THF (20 ml) at 0° C. was added BH₃.THF (40 ml, 1.0 Min THF). The mixture was stirred at room temperature for 1h. To work up,THF was evaporated on a rotavap. The residue was treated with water (100ml) Acidified and extracted with ether (2×100 ml). Removal of thesolvent under reduced pressure gave2-(3,4-methylenedioxy)phenyl-1-ethanol as an oil (4.7 g, 98% yield).

B. 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane

To a stirred solution of 2-(3,4-methylenedioxy)phenyl-1-ethanol (1.68 g,10 mmol) in dry pyridine was added acetic anhydride and the resultantreaction mixture was stirred at 80° C. for 1 h. The reaction mixture waspoured into ice-water and was extracted with ether (2×75 ml). Thecombined ether extract was washed with water (2×50 ml), 5% Hcl (2×50 ml)and then with 5% NaHCO₃ (2×50 ml). The organic layer was dried overmagnesium sulfate and the solvent was removed under reduced pressure togive 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane as a solid (1.7 g,81% yield).

C. 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane

To a stirred solution of 1-acetoxy-2-[(3,4-methylenedioxy)phenyl]ethane(1.7 g, 8.09 mmol) in acetic acid (10 ml) was added, dropwise,concentrated HNO₃ (4.5 ml). This was stirred at room temperature for 30min. The reaction mixture was poured into water (100 ml). Theprecipitated solid was filtered, washed with water and dried under highvacuum to get 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane(1.8 g, 88% yield).

D. 1-acetoxy-2-[(3,4-methylenedioxy)-6-aminophenyl]ethane

The solution of 1-acetoxy-2-[(3,4-methylenedioxy)-6-nitrophenyl]ethane(0.8 g, 3.13 mmol) in ethyl acetate (25 ml) was subjected to catalytichydrogenation using 10% palladium on carbon (100 mg) at 50 psi for 30min. The catalyst was filtered and the solvent was removed under reducedpressure to give 1-acetoxy-2-[(3,4-methylenedioxy)-6-aminophenyl]ethaneas a solid (0.69 g, 98% yield).

E.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 87. The crude product waspurified by preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamideas a dull yellow powder (12% yield, m.p. 78-82° C.).

EXAMPLE 173N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide

To a stirred solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamide(35 mg, 0.066 mmol) in methanol was added NaOH powder (40 mg) andstirred at room temperature for 30 min. HPLC analysis showed completeconsumption of starting material. The reaction mixture was diluted withwater and acidified to pH 2-3. This was extracted with ethyl acetate(2×25 ml). The combined organic layer was dried over magnesium sulfateand the solvent removed under reduced pressure to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)]phenylaminocarbonyl-3-thiophenesulfonamideas a solid (84% yield, m.p. 47-52° C.).

EXAMPLE 174N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide

A. Methyl 2-[3,4-(methylenedioxy)phenoxylacetate and2-[3,4-(methylenedioxy)phenoxy]acetic acid

The mixture of sesamol (13.8 g, 100 mmol, methyl bromoacetate (15.3 g,100 mmol) and potassium carbonate in acetone (200 ml) was refluxed for24 h with stirring. Acetone was removed under reduced pressure. Theresidue was dissolved in water (200 ml) and was extracted with ether(2×100 ml). The combined organic layer was dried over magnesium sulfateand the solvent removed under reduced pressure to give methyl2-[3,4-(methylenedioxy)phenoxylacetate as an oil (12 g, 57% yield). Theaqueous phase was neutralized to pH 2-3 with concentrated HCl and theprecipitated solid was filtered to get2-[3,4-(methylenedioxy)phenoxylacetic acid as a solid (6 g, 31% yield).

B. 2-3,4-(methylenedioxy)phenoxy-1-ethanol

2-(3,4-methylenedioxy)phenoxy-1-ethanol was synthesized in the samemanner as for Example 172(A) using2-[3,4-(methylenedioxy)-phenoxylacetic acid and BH₃.THF complex. Thereaction was carried out for 12 hours at room temperature (98% yield).

C. 1-acetoxy-2-[3,4-(methylenedioxy)phenoxy]ethane

1-Acetoxy-2-[3,4-(methylenedioxy)phenoxylethane was synthesized in thesame manner as for Example 172(B) by acetylation of2-(3,4-methylenedioxy)phenoxy-1-ethanol using acetic anhydride andpyridine (92% yield).

D. 1-acetoxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy]ethane

1-acetoxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy]ethane was synthesizedin the same manner as for Example 172(C) by nitration of1-acetoxy-2-[3,4-(methylenedioxy)phenoxy]ethane. The reaction wascarried out between 0° C. and 5° C. for 30 min (78% yield).

E. 1-acetoxy-2-[3,4-(methylenedioxy)-6-aminophenoxy]ethane

1-acetoxy-2-[3,4-(methylenedioxy)-6-aminophenoxy]ethane was synthesizedin the same manner as for Example 172(D) by reduction of1-acetoxy-2-[3,4-(methylenedioxy)-6-nitrophenoxy]ethane (100% yield).

F.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 87 using1-acetoxy-2-[3,4-(methylenedioxy)-6-aminophenoxylethane andN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide.The crude product was purified by preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamideas a dull yellow powder (21% yield, m.p. 117-119° C.).

EXAMPLE 175N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 173 by basic hydrolysis ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-acetoxyethoxy)]phenylaminocarbonyl-3-thiophenesulfonamide(86% yield, m.p. 158-161° C.).

EXAMPLE 176N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide

A.N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-carboxylthiophene-3-sulfonamide

To a mixture ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxylthiophene-3-sulfonamide(3.23 g, 100 mmol) and diisopropylethyl amine (3 ml) in ethyl acetate(20 ml) was added methoxyethoxymethyl chloride and the resultantreaction mixture was stirred at room temperature for 12 hours. This wasdiluted with ethyl acetate (100 ml) and washed with 1 N HCl (2×50 ml).The organic layer was dried over magnesium sulfate and the solventremoved under reduced pressure to giveN-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(carbomethoxy)thiophene-3-sulfonamideas light brown oil.

The crudeN-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)-2-(carbomethoxy)thiophene-3-sulfonamidewas dissolved in methanol (50 ml) and potassium hydroxide (5 g) andwater (5 ml) were added. The reaction mixture was stirred at roomtemperature for 12 hours and extracted with ethyl acetate (2×50 ml). Theaqueous phase was neutralized to pH 2-3 and was extracted with ethylacetate (2×50 ml). The combined organic layer was dried over magnesiumsulfate and solvent removed to giveN-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-carboxylthiophene-3-sulfonamideas light brown solid (3.5 g, 85% yield).

B. 4—Carbomethoxy-2,6-dimethylaniline

To a warm solution of 3,5-dimethyl benzoic acid (5 g, 33.33 mmol) inacetic acid (30 ml) was added fuming nitric acid (30 ml), dropwise.After completion of the addition the reaction mixture was warmed with aheat gun. This was stirred for an additional 2 hours during which perioda solid was precipitated. The reaction mixture was diluted with water(200 ml) and filtered. The solid was dried under reduced pressure.

To the above solid was added 20 ml of oxalyl chloride and a catalyticamount of DMF (2 drops). This was stirred at room temperature for 3hours during which period a clear solution was formed. Excess oxalylchloride was removed under reduced pressure to give yellow solid.

To the yellow solid was added dry methanol (100 ml) and the mixturestirred at room temperature for 1 hour. Excess methanol was removedunder reduced pressure and the residue dissolved in ether (200 ml). Thiswas washed with water (100 ml) followed by saturated NaHCO₃ solution(100 ml). The organic layer was dried over magnesium sulfate and thesolvent removed giving 4-carbomethoxy-2,6-dimethylnitrobenzene as ayellow solid (5.8 g, 83% yield).

4-Carbomethoxy-2,6-dimethylnitrobenzene (2 g, 9.5 mmol) was dissolved inethyl acetate (20 ml) and subjected to catalytic hydrogenation using 10%palladium on carbon (300 mg) at 55 psi for 30 min. The catalyst wasfiltered and solvent removed to give 4-carbomethoxy-2,6-dimethylanilineas a solid (1.7 g, 100% yield).

C.N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-carboxylthiophene-3-sulfonamide(3.5 g, 8.5 mmol) (from step A) was dissolved in oxalyl chloride (5 ml)and a drop of DMF was added. This was stirred at room temperature for 6hours. Excess oxalyl chloride was removed under reduced pressure and themixture dried under high vacuum.

To a solution of 4-Carbomethoxy-2,6-dimethylaniline (0.9 g) (from stepB) and triethyl amine (2 ml) in methylene chloride (20 ml) at 0° C. wasadded the acid chloride in 10 ml of methylene chloride (2.4 g, 4.98mmol) prepared in the above step. The reaction mixture was permitted towarm to room tempearture, was diluted with methylene chloride (50 ml)and was washed with 1 N HCl followed by saturated NaHCO₃ solution. Theorganic layer was dried over magnesium sulfate and the solvent removedgiving the crude product. This was purified by column chromatographyusing 4:6 ethyl acetate and hexane as a eluent to giveN-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamidean oil (0.6 g, 20% yield).

N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamide(0.6 g) was dissolved in a mixture of methanol (8 ml) and concentratedHCl (1.5 ml) and the resultant reaction mixture was refluxed understirring for 8 hours. Excess methanol was removed under reduced pressureand the residue dissolved in ethyl acetate (50 ml). This was washed withsaturated sodium chloride solution. The organic layer was dried overmagnesium sulfate and the solvent removed givingN-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methoxycarbonyl-2,6-dimethyl)phenylaminocarbonyl-3-thiophenesulfonamidewhich was crystallized using methylene chloride and hexane (0.23 g, 47%yield, m.p. 152-154° C.).

EXAMPLE 177N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamide

A. (3,4-methylenedioxy)-6-methylaniline

To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20ml) cooled with a cold water bath was added, dropwise, nitric acid (70%,5 ml). The mixture was stirred for 45 min. To work up, water (100 ml)was added and the resulting yellow precipitate was filtered and washedwith water until the aqueous filtrate was colorless. The yellow solidwas dissolved in EtOAc (250 ml) and dried (MgSO₄), and the solid wasfiltered off. The filtrate was subjected to catalytic hydrogenation (10%Pd/C, 1 atm) for 12 hours. The reaction mixture was then filtered offthe catalyst and the filtrate was concentrated on a rotavap to give(3,4-methylenedioxy)-6-methylaniline as a brownish grey solid (5.49 g,87% yield).

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 94 using(3,4-methylenedioxy)-6-methylaniline. The crude product was purified bypreparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylaminocarbonyl-3-thiophenesulfonamideas a yellow solid (45% yield, m.p. 60-62° C.).

EXAMPLE 178N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-aminocarbonyl)phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-aminocarbonyl)phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 94 usingN-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide(Example 151) and ammonium hydroxide. The crude product was purified bypreparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-dimethoxy-6-aminocarbonyl)phenylaminocarbonyl-3-thiophenesulfonamideas yellow powder (66% yield, m.p. 189-192° C.).

EXAMPLE 179N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]-phenylacetyl-3-thiophenesulfonamide

A. (3,4-methylenedioxy)-6-methylbenzyl chloride

To a 1:1 mixture of ethyl ether (100 ml) and conc. HCl (100 ml) at 0° C.was added (3,4-methylenedioxy)toluene (10 ml). Formaldehyde (20 ml, 37%in water) was then added dropwise. The reaction was stirred at 0° C. for2 hours and at room temperature for an additional 10 hours. The reactionmixture was then diluted with ethyl ether (100 ml) and the two layerswere separated. The organic layer was dried (MgSO₄), the solid wasfiltered and the filtrate was concentrated. The residue was then heatedwith hexane (200 ml) and the insolubles were filtered off the hotsolution. The filtrate was concentrated to give a mixture of(3,4-methylenedioxy)-6-methylbenzyl chloride (9.4 g, 63% yield) andbis[(3,4-methylenedioxy)-6-methyl]phenylmethane (3.6 g) as a whitesolid. This mixture was carried on to the next step without furtherpurification.

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as for Example 102 using(3,4-methylenedioxy)-6-methylbenzyl chloride instead of(3,4-methylenedioxy)benzyl chloride. The crude product was purified bypreparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamideas a yellow powder (71% yield, m.p. 42-45° C.)

EXAMPLE 180N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonylaminomethyl]phenylaminocarbonyl-3-thiophenesulfonamide

A. N-(3,4-methylenedioxy)benzyl-methanesulfonamide

To a solution of piperonylamine (6.07 g, 38.95 mmol) and triethylamine(5.37 g, 53.12 mmol) in dichloromethane (100 ml) at 0° C. was addedmethanesulfonyl chloride (4.14 g, 35.41 mmol). The reaction was stirredat 0° C. for 1 hour. The mixture was then diluted with dichloromethane(100 ml) and washed with 1 N HCl (2×100 ml). The organic layer was dried(MgSO₄), the solid was filtered and the filtrate was concentrated togive N-(3,4-methylenedioxy)benzyl-methanesulfonamide as a grey solid(8.4 g, 92% yield).

B. N-[3,4-(methylenedioxy)-6-aminolbenzyl-methanesulfonamide

N-[3,4-(methylenedioxy)-6-amino]benzyl-methanesulfonamide wassynthesized in the same manner as for(3,4-methylenedioxy)-6-methylaniline (Example 177).

C.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonylaminomethyl]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonylaminomethyl]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 94. The crude product wasrecrystalized from acetonitrile and water to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonylaminomethyl]phenylaminocarbonyl-3-thiophenesulfonamideas an off-white solid (13% yield, m.p. 147-150° C.).

EXAMPLE 181N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyanomethyl]phenylaminocarbonyl-3-thiophenesulfonamide

A. 13,4-(methylenedioxy)-6-amino]phenylacetonitrile

[3,4-(methylenedioxy)-6-amino]phenylacetonitrile was synthesized in thesame manner as for (3,4-methylenedioxy)-6-methylaniline (Example 177).

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyanomethyl]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyanomethyl]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as in Example 94. The crude productwas recrystalized from acetonitrile/water to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyanomethyl]phenylaminocarbonyl-3-thiophenesulfonamideas a red-brownish powder (15% yield, m.p. 190-193° C.).

EXAMPLE 182N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(3-hydroxypropyl)]phenylaminocarbonyl-3-thiophenesulfonamide

A. 3-(3,4-methylenedioxy)phenyl-1-propanol

To a solution of 3-(3,4-methylenedioxy)phenylpropanoic acid (5 g, 25.75mmol) in anhydrous •THF (20 ml) at 0° C. was added BH₃.THF (51.5 ml, 1.0M in THF, 51.5 mmol). The mixture was refluxed for 1 hour. Then the THFwas evaporated on a rotavap. The residue was treated with methanol (20ml) and the solution was concentrated. This process was repeated 6 timesto give 3-(3,4-methylenedioxy)phenyl-1-propanol as an oil (4.7 g,˜100yield).

B. 3-[3,4-(methylenedioxy)-6-amino]phenyl-1-propanol

3-[3,4-(methylenedioxy)-6-amino]phenyl-1-propanol was synthesized in thesame manner as for (3,4-methylenedioxy)-6-methylaniline (Example 177).

C.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(3-hydroxypropyl)]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(3-hydroxypropyl)]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 94. The crude product waspurified by preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(3-hydroxypropyl)]phenylaminocarbonyl-3-thiophenesulfonamideas a dull yellow powder (18% yield, m.p. 66-69° C.).

EXAMPLE 183N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano]phenylacetyl-3-thiophenesulfonamide

A. Methyl (3,4-methylenedioxy)phenylacetate

Methyl (3,4-methylenedioxy)phenylacetate was prepared as described byknown methods (see, Rachele (1963) Journal of Organic Chemistry28:2898).

B. Methyl 6-bromo-(3,4-methylenedioxy)phenylacetate

To a solution of methyl (3,4-methylenedioxy)phenylacetate (5 g, 25.8mmol) in acetic acid (15 ml) was added, dropwise, bromine until ared-brown color persisted. After stirring at RT for 30 minutes, thereaction mixture was partitioned between water (200 ml) and ether (200ml). The organic layer was washed with water (3×200 ml), dried (MgSO₄),the solid was filtered off and the filtrate was concentrated to givemethyl 6-bromo-(3,4-methylenedioxy)phenylacetate as an oil (5.9 g, 84%yield).

C. Methyl (3,4-methylenedioxy)-6-cyanophenylacetate

Methyl (3,4-methylenedioxy)-6-cyanophenylacetate was prepared asdescribed by L. Friedman and H. Shechter in the Journal of OrganicChemistry 26:2522 (1961).

D. t-Butyl (3,4-methylenedioxy)-6-cyanophenylacetate

To a solution of methyl (3,4-methylenedioxy)-6-cyanophenylacetate (5 g,18.32 mmol) in methanol (100 ml) was added 1 N NaOH (50 ml). Thereaction was stirred at room temperature for 1.5 hours. Methanol wasthen stripped off on a rotavap. The aqueous residue was acidified withconc. HCl to pH˜1 and extracted with ethyl acetate. The organic layerwas dried (MgSO₄), the solid was filtered and the filtrate wasconcentrated to give a solid. The solid was treated with thionylchloride (50 ml) and the mixture was refluxed for 10 min before thevolatiles were stripped off on a rotavap. The residue was dissolved indichloromethane (15 ml) and the solution was added dropwise to asolution of 2-methyl-2-propanol (6.8 g, 91.6 mmol) and triethylamine(9.3 g, 91.6 mmol) in dichloromethane (100 ml) at 0° C. The mixture wasstirred at 0° C. for 1 hour and at room temperature for 2 hours. Themixture was then washed with water (3×150 ml). The organic layer wasdried (MgSO₄), the solid was filtered and the filtrate was concentratedto give t-butyl (3,4-methylenedioxy)-6-cyanophenylacetate as a solid(335 mg, 7% yield).

E.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano]phenylacetyl-3-thiophenesulfonamide

To a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-carboxyl-3-thiophenesulfonamide(2.78 g, 8.63 mmol) in anhydrous DMF (30 ml) was addedcarbonyldiimidazole (1.40 g, 8.63 mmol). The mixture was stirred at roomtemperature for 20 min to give mixture I.

To a solution of t-butyl (3,4-methylenedioxy)-6-cyanophenylacetate (1.5g, 5.75 mmol) in anhydrous DMF (15 ml) was added NaH (1.2 g, 60%dispersion in mineral oil, 29.9 mmol) at 0° C. The mixture was stirredat room temperature for 30 min to give mixture II. Mixture I wassyringed to mixture II at 0° C. and the resulting mixture was stirred at0° C. for 1 hour and at RT for 10 hours. The crude mixture was poured toa 2:2:1 mixture of acetonitrile/water/conc. HCl and the resultingmixture was heated at 40° C. for 12 hours. Acetonitrile was then removedon a rotavap and the aqueous residue was partitioned between ethylacetate (200 ml) and 1 N HCl (150 ml). The organic layer was washed with1 N HCl (3×150 ml) and dried (MgSO₄), the solid was filtered off and thefiltrate was concentrated. The residue was purified by preparative HPLCto giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano]phenylacetyl-3-thiophenesulfonamideas a light dull yellow powder (450 mg, 17% yield, m.p. 105-108° C.).

EXAMPLE 184N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dimethylaminocarbonylmethyl]phenylaminocarbonyl-3-thiophenesulfonamide

A. N,N-dimethyl (3,4-methylenedioxy)phenylacetamide

N,N-dimethyl (3,4-methylenedioxy)phenylacetamide was synthesized in thesame manner as described in Example 94.

B. N,N-dimethyl (3,4-methylenedioxy)-6-aminophenylacetamide

N,N-dimethyl (3,4-methylenedioxy)-6-aminophenylacetamide was synthesizedin the same manner as (3,4-methylenedioxy)-6-methylaniline (see Example177).

C.N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dimethylaminocarbonylmethyl]phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dimethylaminocarbonylmethyl]phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 94. The crude product wasrecrystalized from acetonitrile/water to give N-(4-Fchloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-dimethylaminocarbonylmethyl]phenylaminocarbonyl-3-thiophenesulfonamideas a greyish powder (400 mg, 19% yield, m.p. 190-193° C.).

EXAMPLE 185N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]benzylhydroxyimino-3-thiophenesulfonamide

ToN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide(100 mg) was added NH₂)OH•HCl (300 mg) and water (15 ml). After stirringfor 5 min, NaOH pellet (300 mg) and methanol (2 ml) were added. The warmmixture was heated at 80° C. for 20 min and was cooled to 0° C. It wasthen poured into a dilute HCl solution (˜30 ml). The resulting whiteprecipitate was filtered to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]benzylhydroxyimino-3-thiophenesulfonamideas a white solid (72 mg, 70% yield, m.p. 154-156° C.).

EXAMPLE 186 N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-acetoxy-2-cis-[3,4-(methylenedioxy)-6-methyl]phenyl}vinyl-3-thiophenesulfonamide

To a solution ofN-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamide(50 mg, 0.11 mmol) in anhydrous DMF (1 ml) was added NaH (11 mg, 60%dispersion in mineral oil, 0.275 mmol). After stirring at roomtemperature for 5 min, acetic anhydride (16.8 mg, 0.165 mmol) was added.After stirring at room temperature for an additional 10 min., themixture was poured into dilute HCl solution and the resultingprecipitate was filtered to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-acetoxy-2-cis-[3,4-(methylenedioxy)-6-methyl]phenyl}vinyl-3-thiophenesulfonamideas a yellowish powder (40 mg, 73%, m.p. 55-58° C.).

EXAMPLE 187N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-cyano)phenylaminocarbonyl-3-thiophenesulfonamide

A. 2-amino-3,4,5-trimethoxybenzonitrile

2-amino-3,4,5-trimethoxybenzonitrile was synthesized in the same manneras (3,4-methylenedioxy)-6-methylaniline (see Example 177), and the crudeproduct was recrystalized from methanol/water to give a yellow powder(13% yield).

B.N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-cyano)phenylaminocarbonyl-3-thiophenesulfonamide

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-cyano)phenylaminocarbonyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 148. The crude product waspurified via preparative HPLC to giveN-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-cyano)phenylaminocarbonyl-3-thiophenesulfonamideas a yellow powder (180 mg, 10% yield, m.p. 88-90° C.).

EXAMPLE 188N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]-phenylacetyl-3-thiophenesulfonamide

N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 179. The crude product waspurified via preparative HPLC to giveN-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamideas a yellow powder (417 mg, 14% yield, m.p. 45-50° C.).

EXAMPLE 189N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]-phenylacetyl-3-thiophenesulfonamide

N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamidewas synthesized in the same manner as Example 179. The crude product waspurified via preparative HPLC to giveN-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methyl]phenylacetyl-3-thiophenesulfonamideas a yellowish powder (330 mg, 16% yield, m.p. 46-50° C.).

EXAMPLE 190

Other compounds that have been prepared by the above methods or routinemodifications thereof, include, but are not limited to:

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)methyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)-thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)acetyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-t4-methylphenethyl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(5-methyl-3-isoxazolyl)amino-carbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3-hydroxyl-6-pyridazinyl)aminocarbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-{[3,4-(methylenedioxy)phenoxy]methyl}-thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenethyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)-trans-styryl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)phenethyl]thiophene-3-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-(4-tolylacetylphenyl)thiophene-3-sulfonamide,N-(3,4-dimethyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-hydroxy-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamideand others, including those set forth in TABLE 1 that are notspecifically exemplified herein.

For example,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5-(methylenedioxy)cinnamyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-(hydroxymethyl)-4,5-(methylenedioxy)-cinnamyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-{2-[(tetrahydro-4H-pyran-2-ylxoy)methyl]-4,5-(methylenedioxy)cinnamyl}-thiophene-2-sultonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimethylcinnamyl)thiophene-2-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)-trans-styryl]thiophene-2-sulfonamide.N-(4-bromo-3-methyl-5-isoxazolyl)-3-[2-methyl-4,5-(methylenedioxy)phenethyl]thiophene-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylphenethyl)thiophene-3-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)-phenethyl]thiophene-3-sulfonamide(see, Example 159).N-(4-bromo-3-methyl-5-isoxazolyl)-3-{[2-propyl-4,5-(methylenedioxy)-phenoxy]methyl}thiophene-2-sulfonamidehas been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)-methyl]thiophene-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-3-{[3,4-(methylenedioxy)phenoxy]methyl}thiophene-2-sulfonamide.N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenethyl]thiophene-3-sulfonamidehas been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenethyl]thiophene-3-sulfonamide.Compounds, such asN-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methoxyphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methoxyphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methoxyphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-ethylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-propylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-propylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-butylphenyl)-thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2,4-dimethylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-butylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-pentylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methyl-4-propylphenyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-iso-butyl-2-methylphenyl)-thiophene-2-sulfonamideandN-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-isopentyl-2-methylphenyl)thiophene-2-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-3-[(3,4-methylenedioxy)phenyl]thiophene-2-sulfonamide(see, Example 125).

N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenethyl]thiophene-3-sulfonamidehas been prepared in the same manner asN-(4-Bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide(Example 128).N-(4-bromo-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)cinnamyl]thiophene-3-sulfonamidehas been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methyl)(cinnamyl)]thiophene-3-sulfonamide (Example 158).

N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)phenoxy]methyl}thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenoxy)methyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-propylphenoxy]methyl}thiophene-3-sulfonamidehave been prepared in the same manner asN-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide(Example 160).

Any corresponding N-(4-halo-3-methyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(3,4-dimethyl-5-isoxazolyl),N-(4-halo-5-methyl-3-isoxazolyl), N-(4-halo-3-methyl-5-isoxazolyl),N-(4,5-dimethyl-3-isoxazolyl) derivative of any of these compounds orany compound disclosed herein may also be prepared and used as describedherein.

EXAMPLE 191

Other compounds that can be prepared by the above methods or routinemodifications thereof, include, but are not limited to:

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-acetylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methoxycarbonylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-carboxylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methanesulfonylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(cyanomethyl)phenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-acetylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methoxycarbonylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-carboxylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methanesulfonylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-cyanophenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-cyanomethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(2-hydroxyethyl)phenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-acetyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxycarbonyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-carboxyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonyl-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(cyanomethyl)-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)-2-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-cyano-6-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-cyanophenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-acetyl-6-methylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-acetylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyanomethyl-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxylmethyl)-2,4,6-trimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6-dimethylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-carboxyl-2,6-dimethylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(hydroxymethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(cyanomethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxylmethyl)-2,6-dimethylphenylaminocarbonyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6-dimethylphenylaminocarbonyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-acetylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methoxycarbonylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-carboxylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,3,4-trimethoxy-6-methanesulfonylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(cyanomethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2,3,4-trimethoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-acetylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-methoxycarbonylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-carboxylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy-2-methoxy-6-methanesulfonyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(cyano)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(cyanomethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-methoxy-6-(2-hydroxyethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2,6-dimethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-acetyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxycarbonyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-carboxyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methanesulfonyl-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-cyano-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(cyanomethyl)-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-(2-hydroxyethyl)-2-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-cyano-6-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-cyanophenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-2-acetyl-6-methylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)-6-methoxy-2-acetylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-carboxyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-hydroxymethyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-methanesulfonyl-2,4,6-trimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(cyanomethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(2-hydroxyethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3-(carboxylmethyl)-2,4,6-trimethylphenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-cyano-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-f4-carboxyl-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-hydroxymethyl-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(2-hydroxyethyl)-2,6-(dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-cyanomethyl-2,6-(dimethyl)phenylacetyl]thiophene-3-sulfonamide,

N-(4-chloro-3-methyl-5-isoxazolyl)-2-[4-(carboxylmethyl)-2,6-dimethylphenylacetyl]thiophene-3-sulfonamide,and

N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-methanesulfonyl-2,6-dimethylphenylacetyl)thiophene-3-sulfonamide.

EXAMPLE 192

Other compounds, having activity generally at IC₅₀ concentrations of 10μM or substantially less for ET_(A) or ET_(B) receptors, in which Ar²contains a heterocyclic ring, such as thienyl-, furyl- andpyrrole-sulfonamides of interest herein, can be or have been prepared(see, e.g., TABLE 1) by methods analogous to those set forth in theabove Examples. Such compounds include, but are not limited to thefollowing compounds:N-(4-bromo-3-methyl-5-isoxazolyl)-2-carboxyl-1-methylindole-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-oxacyclohexyl)oxycarbonyl]thiophene-3-sulfonamide,2-[3,4-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-{2-[3,4-(methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamideoxime, N-(4-chloro-3-methyl-5-isoxazolyl)-2-phenylbenzo[b]thiophenesulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-tolyl)aminocarbonyl]-1-methylindole-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-1-[3,4-(methylenedioxy)benzyl]indole-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)carbonyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxyphenyl)acetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-6-methoxy-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)methyl]thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenoxy)methyl]thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(4-methylphenyl)acetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3-methoxyphenyl)acetyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-hydroxy-1-[3,4-(methylenedioxy)benzyl]ethyl}thiophene-3-sulfonamide,N-4-(bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)(4-tolyl)thiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylbenzyl)-5-(4-tolylthiophene-2-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methyl-trans-styryl)-5-(4-tolyl)thiophene-2-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[β,β-(ethylenedioxy)3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[β-(dimethylamino)-3,4-(methylenedioxy)phenethylthiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-{a-hydroxy-[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide;N-(4-chloro-5-methyl-3-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-styrylthiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-styrylthiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(benzoylamino)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(phenyl)methylaminocarbonyl]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(phenylthio)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(hydroxymethyl)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-(carbomethoxy)furan-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2,5-dimethylfuran-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diisopropylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(diethylaminocarbonyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylfuran-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-5-styrylthiophene-2-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-(dimethylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-methoxybenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-phenoxybenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-methoxybenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-isobutylaminobenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-5-benzylaminobenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxy]benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxy]-5-dimethylaminobenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)phenyl]acetyl-5-dimethylaminobenzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylcarbonyl]-N-methylindole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonyl]indole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonyl]-N-methylindole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)phenoxycarbonyl]indole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-N-methylindole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]indole-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyloxycarbonyl]-7-(N,N-dimethylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-(N,N-dimethylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzoyl]-7-(N,N-dimethyl)amino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-7-(N,N-dimethylamino)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-7-(methoxycarbonyl)benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]-7-(methoxy)-benzo[b]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-7-(methoxy)benzo[b]thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methylphenethyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-2-(trans-4-methylcinnamyl)thiophene-3-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(4-methylphenethyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(3-methylphenethyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(2-methylphenethyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(trans-4-methylcinnamyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(trans-3-methylcinnamyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-(trans-2-methylcinnamyl)thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-[(4-methylphenoxy)-methyl]thiophene-2-sulfonamide;N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenethyl]thiophene-2-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{(3,4-(dimethoxy)phenyl]acetyl)}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,5-dimethoxyphenyl)acetyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4,5-trimethoxyphenyl)acetyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylsulfonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylsulfenyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzylsulfenyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(dimethylamino)-2-[3,4-(methylene-dioxy)phenyl}ethylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-methylamino)-2-[3,4-(methylenedioxy)phenyl]ethyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(methoxylimino)-2-[3,4-(methylenedioxy)phenyl]ethyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{1-(carboxyl)-2-[3,4-(methylenedioxy)phenyl]-ethyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-(carboxyl)-1-[3,4-(methylenedioxy)benzyl]vinyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{3-[3,4-(methylenedioxy)phenyl]-1,2,4-oxadiazol-5-lyl}thiophene-3-sulfonamide;andN-(4-chloro-3-methyl-5-isoxazolyl-2-{3-[3,4-(methylenedioxy)benzyl]-1,2,4-oxadiazol-5-lyl}thiophene-3-sulfonamide.

Additional compounds include, but are not limited to:N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4,5-(methylenedioxy)-phenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-carboxylphenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-(methoxycarbonyl]phenyl}aminocarbonyl)thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-cyano-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-hydroxymethyl)phenyl]aminocarbonylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-acetyl-4-methylphenyl]aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4-methylphenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-carboxyl-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methoxycarbonyl-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-cyano-4-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(hydroxymethyl)-4-methylphenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimethoxy-6-acetylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-(methanesulfonyl)-4,5-dimethoxyphenyl]aminocarbonyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-carboxylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarboxyl)phenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano(4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4,5-dimethoxy-2-hydroxymethyl)phenylaminocarbonylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-acetyl-4,5-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[2-methanesulfonyl)-4,5-(methylenedioxy)phenyl]-acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[carboxyl4,5-(methylenedioxy)-2-phenylacetylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[4,5-(methylenedioxy)-2-methoxycarbonylphenyl]acetylthiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-cyano[4,5-(methylenedioxy)-phenyl]acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{2-hydroxymethyl[4,5-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethoxy)phenyl)aminocarbonyl]thiophene-3sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-metheylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,3-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,6-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(3,4-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,5-dimethylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,5-dimethyl)phenylaminocarbonythiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-methoxy-6-methylphenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2,4,6-trimethylphenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-ethyl(4-methoxy-)phenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-isopropyl-4-methoxy-phenyl)aminocarbonyl]thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(2-propyl-4-methoxy-phenyl)aminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-biphenylaminocarbonyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methylphenyl)acetyl]-thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-ethylphenyl)-acetyl}thiophene-3-sulfonamide;N-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)-6-methoxyphenyl]acetyl}thiophene-3-sulfonamide.

EXAMPLE 193 Assays for Identifying Compounds that Exhibit EndothelinAntagonistic and/or Agonist Activity

Compounds that are potential endothelin antagonists are identified bytesting their ability to compete with ¹²⁵I-labeled ET-1 for binding tohuman ET_(A) receptors or ET_(B) receptors present on isolated cellmembranes. The effectiveness of the test compound as an antagonist oragonist of the biological tissue response of endothelin can also beassessed by measuring the effect on endothelin induced contraction ofisolated rat thoracic aortic rings. The ability of the compounds to actas antagonists or agonists for ET_(B) receptors can be assess by testingthe ability of the compounds are to inhibit endothelin-1 inducedprostacyclin release from cultured bovine aortic endothelial cells.

A. Endothelin binding inhibition—Binding Test #1: Inhibition of bindingto ET_(A) receptors

TE 671 cells (ATCC Accession No. HTB 139) express ET_(A) receptors.These cells were grown to confluence in T-175 flasks. Cells frommultiple flasks were collected by scraping, pooled and centrifuged for10 min at 190×g. The cells were resuspended in phosphate buffered saline(PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. Thesuspension was centrifuged at 4° C. at 57,800×g for 15 min, the pelletwas resuspended in 5 ml of buffer A (5 mM HEPES buffer, pH 7.4containing aprotinin (100 KIU/ml)) and then frozen and thawed once. 5 mlof Buffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCl₂ and 0.001%deoxyribonuclease Type 1) was added, the suspension mixed by inversionand then incubated at 37° C. for 30 minutes. The mixture was centrifugedat 57,800×g as described above, the pellet washed twice with buffer Aand then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml) to give a final protein concentration of 2 mg/mland stored at −70° C. until use.

The membrane suspension was diluted with binding buffer (30 mM HEPESbuffer, pH 7.4 containing 150 mM NaCl, 5 mM MgCl₂, 0.5% Bacitracin) to aconcentration of 8 μg/50 μl. ¹²⁵I-endothelin-1 (3,000 cpm, 50 mL) wasadded to 50 μL of either: (A) endothelin-1 (for non specific binding) togive a final concentration 80 nM); (B) binding buffer (for totalbinding); or (C) a test compound (final concentration 1 nM to 100 μM).The membrane suspension (50 μL), containing up to 8 μg of membraneprotein, was added to each of (A), (B), or (C). Mixtures were shaken,and incubated at 4° C. for 16-18 hours, and then centrifuged at 4° C.for 25 min at 2,500×g. Alternatively, the incubation was conducted at24° C. When incubated at 24° C., the IC₅₀ concentrations are 2- to10-fold higher than when the incubation is conducted at 4° C. This, mustbe kept in mind when comparing IC ₅₀ concentrations among compoundsprovided herein.

The supernatant, containing unbound radioactivity, was decanted and thepellet counted on a Genesys multiwell gamma counter. The degree ofinhibition of binding (D) was calculated according to the followingequation:${\% \quad D} = {100 - {\frac{(C) - (A)}{(B) - (A)} \times 100}}$

Each test was generally performed in triplicate.

B. Endothelin binding inhibition—Binding Test #2: Inhibition of bindingto ET_(B) receptors

COS7 cells were transfected with DNA encoding the ET_(B) receptor, Theresulting cells, which express the human ET_(B) receptor, were grown toconfluence in T-150 flasks. Membrane was prepared as described above.The binding assay was performed as described above using the membranepreparation diluted with binding buffer to a concentration of 1 μg/50μl.

Briefly, the COS7 cells, described above, that had been transfected withDNA encoding the ET_(B) receptor and express the human ET_(B) receptoron their surfaces were grown to confluence in T-175 flasks. Cells frommultiple flasks were collected by scraping, pooled and centrifuged for10 min at 190×g. The cells were resuspended in phosphate buffered saline(PBS) containing 10 mM EDTA using a Tenbroeck homogenizer. Thesuspension was centrifuged at 4° C. 57,800×g for 15 min, the pellet wasresuspended in 5 ml of buffer A (5 mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml)) and then frozen and thawed once. Five ml ofBuffer B (5 mM HEPES Buffer, pH 7.4 containing 10 mM MnCl₂ and 0.001%deoxyribonuclease Type 1) was added, the suspension mixed by inversionand then incubated at 37° C. for 30 minutes. The mixture was centrifugedat 57,800×g as described above, the pellet washed twice with buffer Aand then resuspended in buffer C (30 mM HEPES buffer, pH 7.4 containingaprotinin (100 KIU/ml) to give a final protein concentration of 2 mg/ml.

The binding assay was performed as described above using the membranepreparation diluted to give 1 μg/50 μl of binding buffer.

C. Test for activity against endothelin-induced contraction of isolatedrat thoracic aortic rings

The effectiveness of the test compound as an antagonist or agonist ofthe biological tissue response of endothelin also is assessed bymeasuring the effect on endothelin induced contraction of isolated ratthoracic aortic rings (see, e.g., Borges et al. (1989) Eur. J.Pharmacol. 165:223-230) or by measuring the ability to contract thetissue when added alone.

Compounds to be tested are prepared as 100 μM stocks. If necessary toeffect dissolution, the compounds are first dissolved in a minimumamount of DMSO and diluted with 150 mM NaCl. Because DMSO can causerelaxation of the aortic ring, control solutions containing varyingconcentrations of DMSO were tested.

The thoracic portion of the adult rat aorta is excised, the endotheliumabraded by gentle rubbing and then cut into 3 mm ring segments. Segmentsare suspended under a 2 g preload in a 10 ml organ bath filled withKrebs'—Henseleit solution saturated with a gas mixture of 95% O₂ and 5%CO₂ (118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄, 25 mM NaHCO₃,2.5 mM CaCl₂, 10 mM D-glucose).

There is a correlation between activity as an antagonist ofendothelin-induced thoracic aortic ring contraction and activity as aninhibitor of binding of endothelin to endothelin receptors. The pA₂ is alinear function of the log of the IC₅₀.

D. Assay for identifying compounds that have agonist and/or antagonisticactivity against ET_(B) receptors

1. Stimulation of prostacyclin release

Since endothelin-1 stimulates the release of prostacyclin from culturedbovine aortic endothelial cells, the compounds that have agonist orantagonist activity are identified by their ability to inhibitendothelin-1 induced prostacyclin release from such endothelial cells bymeasuring 6-keto PGF_(1a) substantially as described by (Filep et al.(1991) Biochem. Biophys. Res. Commun. 177 171-176. Bovine aortic cellsare obtained from collagenase-treated bovine aorta, seeded into cultureplates, grown in Medium 199 supplemented with heat inactivated 15% fetalcalf serum, and L-glutamine (2 mM), penicillin, streptomycin andfungizone, and i subcultured at least four times. The cells are thenseeded in six-well plates in the same medium. Eight hours before theassay, after the cells reach confluence, the medium is replaced. Thecells are then incubated with a) medium alone, b) medium containingendothelin-1 (10 nM), c) test compound alone, and d) testcompound+endothelin-1 (10 nM).

After a 15 min incubation, the medium is removed from each well and theconcentrations of 6-keto PGF_(1a) are measured by a direct immunoassay.Prostacyclin production is calculated as the difference between theamount of 6-keto PGF_(1a) released by the cells challenged with theendothelin-1 minus the amount released by identically treatedunchallenged cells. Compounds that stimulate 6-keto PGF_(1a) releasepossess agonist activity and those which inhibit endothelin-1 6-ketoPGF_(1a) release possess antagonist activity.

2. Inhibition of sarafotoxin 6c induced contraction

Sarafotoxin 6c is a specific ET_(B) antagonist that contracts rat fundalstomach strips. The effectiveness of tests compounds to inhibit thissarafotoxin 6c-induced contraction of rat fundal stomach strips is usedas a measure ET_(B) antagonist activity. Two isolated rat fundal stomachstrips are suspended under a 1 g load in a 10 ml organ bath filled withKrebs'—Henseleit solution containing 10 μMcyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123; see, U.S. Pat. No. 5,114,918to Ishikawa et al.), 5 μM indomethacin, and saturated with a gas mixtureof 95% O₂/5% CO₂. Changes in tension are measured isometrically andrecorded using a Grass Polygraph coupled to a force transducer.Sarafotoxin 6c is added cumulatively to one strip while the second stripis preincubated for 15 min with a test compound prior to addition ofcumulative doses of sarafotoxin 6c. The effects of the test compounds onthe concentration-response curve for sarafotoxin 6c are examined.

E. Deoxycorticosterone acetate (DOCA)-salt hypertensive rat model forassessing in vivo activity of selected compounds

Selected compounds disclosed herein have been tested for activity in thedeoxycorticosterone acetate (DOCA)-salt hypertensive rat model. Toperform these tests, silastic MDX4-4210 elastomer implants containing 47mg (DOCA) were prepared according to the method of Ornmsbee et al.((1973) the J. Pharm. Sci. 62:255-257). Briefly, DOCA is incorporatedinto silicon rubber implants for sustained release. To prepare theimplants the DOCA is incorporated into unpolymerized silicone rubber,catalyst is added and the mixture is cast in a hemicylindrical shape.

Sprague Dawley rats (7-8 weeks old) were unilaterally nephrectomizedunder ketamine anesthesia and a DOCA-implant was placed on the leftlateral dorsal abdomen of the animal. The rats were allowed to recoverfor three weeks. During recovery they were permitted free access tonormal rat chow and 0.9% NaCl drinking solution in place of drinkingwater. The rats develop hypertension within 3 weeks.

All animals were used in the tests between 21 and 30 days post surgery.The mean arterial blood pressure in these animals ranged from 165-200 mmHg.

On the day of experimentation, catheters were inserted under brevitalanesthesia into the right femoral artery for measurement of bloodpressure, and into the right femoral vein for administration of aselected compound. The animals were placed in a restrainer and allowedto recover for a minimum of 60 min or until a steady mean arterial bloodpressure was recorded. At that time, the selected compound or controlvehicle was administered either intravenously, as a 60 minute infusion,or orally by oral gavage. Blood pressure was recorded continuously for afurther 10 hrs.

F. Effect of Intravenous administration on ET-1-induced pressorresponses in conscious, autonomically blocked rats; a model forassessing in vivo activity of selected compounds

Male Sprague Dawley rats (250-450 g) were anesthetized (Brevital 50mg/kg, IP) and cannulae were placed in the femoral artery to measuremean arterial pressure (MAP) and in the femoral vein for intravenousdrug administration. Animals were placed in a restrainer and allowed toregain consciousness. Thirty minutes later autonomic blockade wasadministered (atropine methyl nitrate, 3 mg/kg, IV, followed bypropranalol, 2 mg/kg, IV). An hour later animals received a bolusinjection of vehicle (0.5 ml) followed thirty minutes later byintravenous bolus administration of ET-1 (Control, 1 μg/kg). Followingrecovery from this challenge, test-compounds were administered byintravenous bolus administration (0.5 ml) and then re-challenged withET-1 thirty minutes later. Results are expressed as the percentinhibition of the ET-1-induced pressor response after administration ofthe test compound compared to the pressor response induced by thecontrol ET-1 challenge. In some cases a third ET-1 challenge wasadministered ninety minutes after administration of the test compound.

G. Results

1. In vitro

The IC₅₀ for each of the compounds of the preceding Examples for ET_(A)and ET_(B) receptors has been measured. Almost all of the compounds havean IC₅₀ of less than 10 μM for either or both of the ET_(A) and ET_(B)receptors. Many of the compounds have an IC₅₀ less than about 10 μM,others have an IC₅₀ less than about 1 μM and some of the compounds havean IC₅₀ less than about 0.1 μM. A number of the compounds have an IC₅₀for ET_(A) receptors that is substantially less (10 to 100-fold or more)than for ET_(B) receptors, and, thus are selective for ET_(A) receptors.Others of the compounds are ET_(B) selective.

2. In vivo

a. Selected compounds, such asN-(4-chloro-3-methyl-5-isoxazolyl)-2-(N-(4-methyl-phenyl)aminocarbonyl)thiophene-3-sulfonamide,N-(4-bromo-3-methyl-5-isoxazolyl)-2-[3,4-(methylenedioxy)benzyl]benzo[b]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4,-methylenedioxy)benzyl)benzo[b]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[β-hydroxy(3,4-methylenedioxy)phenylethyl]thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3,4-methylenedioxybenzylcarbonyl)thiophene-3-sulfonamide,have been tested in the hypertensive rat model, and were effective indecreasing blood pressure.

b. Selected compounds, such asN-(4-chloro-3-methyl-5-isoxazolyl)-2-{[3,4-(methylenedioxy)phenyl]acetyl}thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-acetyl-4,5-(methylenedioxy)phenyl]aminocarbonyl}thiophene-3-sulfonamide,N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4-methoxy-2-methylphenyl)aminocarbonyl]thiophene-3-sulfonamideandN-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-cyano-4,5-dimethoxyphenyl)aminocarbonyl]thiophene-3-sulfonamide,and-(4-chloro-3-methyl-5-isoxazolyl)-2-[2-methyl-4,5-(methylenedioxy)phenylacetyl]thiophene-3-sulfonamidehave been tested in the autonomically blocked, normotensive rat modeland shown to have substantial activity, reducing pressure about 30% in30 min at dosages as low as 30 mg/kg, and more than 50% at dosages of 60mg/kg. On the average dosages of 30-60 mg/kg of the test compoundresulted in a 40-60% inhibition of pressor response.

Since modifications will be apparent to those of skill in this art, itis intended that this invention be limited only by the scope of theappended claims.

We claim:
 1. A sulfonamide compound of formula (I):

wherein: Ar¹ is a substituted or unsubstituted group, having from 1 to30 carbon atoms, selected from the group consisting of alkyl, alkenyland alkynyl groups, which are straight or branched chains or have cyclicportions; aryl groups; and fused bicyclic or tricyclic rings; and Ar²has formula IV:

in which X is S, O or NR¹¹ in which R¹¹ is hydrogen or has up to about30 carbon atoms and is selected from alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, C(O)R¹⁵ and S(O)_(n)R¹⁵ in which n is 0-2; R¹⁵ ishydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; R¹¹ and R¹⁵are unsubstituted or are substituted with one or more substituents eachselected independently from Z, Z is hydrogen, halide, pseudohalide,alkyl, alkoxy, alkenyl, alkenyloxy, alkynyl, aryl, aryloxy, heteroaryl,heteroaryloxy, a D, L or racemic amino acid, a primary and secondaryamide, an O-glycoside, hexose, ribose, alkylaryl, alkylheteroaryl,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R¹⁶, CO₂R¹⁶, SH, S(O)_(n)R¹⁶ in which n is 0-2, NHOH,NR¹²R¹⁶, NO₂, N₃, OR¹⁶, R¹²NCOR¹⁶, CONR¹²R¹⁶, a sulfonyl chloride,(CH₂)_(x)S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, —(CH₂)_(x)C(O)NHR⁵⁰,—(CH₂)_(x)OH or —(CH₂)_(x)COOH; x is 0 to 6; R¹⁶ is hydrogen, alkyl,alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl, cycloalkynyl, a sulfonyl chloride, S(O)₂NHR⁵⁰,alkylaryl, alkylheteroaryl, —C(O)NHR⁵⁰ or —(CH₂)_(x)OH; R⁵⁰ is H, alkyl,lower alkyl or lower alkoxy; R¹², which is selected independently fromR¹¹ and Z, is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, C(O)R¹⁷ and S(O)_(n)R¹⁷ in which n is 0-2; and R¹⁷ ishydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, aralkoxy, cycloalkyl, cycloalkenyl or cycloalkynyl; each ofR¹¹, R¹², R¹⁵ and R¹⁶ are unsubstituted or substituted with the any ofthe groups set forth for Z; and R⁸, R⁹ and R¹⁰ are each independentlyselected as follows from (i) or (ii): (i) R⁸, R⁹ and R¹⁰, which each ishydrogen or has up to about 50 carbon atoms are each independentlyselected from halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl,aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R¹⁸, acetoxy-(CH═CH)—, CO₂R¹⁸,SH, (CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸, S(O)_(m)R¹⁸,—(CH₂)_(x)C(O)-W-aryl, —(CH₂)_(x)C(O)-W-heteroaryl,—(CH₂)_(x)N(H)-W-aryl, —(CH₂)_(x)N(H)-W-heteroaryl, HNOH, NR¹⁸R¹⁹, NO₂,N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸, in which: R¹⁹ is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, alkoxy, aryloxy,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R²⁰ and S(O)_(n)R²⁰ in which n is 0-2; and R¹⁸ and R²⁰ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkylaryl, heterocyclyl, alkoxy, aryloxy, aralkyl, aralkoxy,cycloalkyl, cycloalkenyl and cycloalkynyl; aryl is a single or two orthree fused rings that has 5 to 7 members in the ring that isunsubstituted or substituted with Z, at one or more positions, eachsubstituent selected independently; heteroaryl a single or two or threefused rings that has 5 to 7 members in each ring, and one to twoheteroatoms in each ring, and is unsubstituted or substituted with Z atone or more positions, each substituent selected independently; W is═C(CH₂)_(x)(halo)2, ═N(H), ═C(CH2)_(x)COOH, ═N(lower alkyl), ═C(O),lower alkyl, alkyl which is straight or branched having 1 to 6 carbons,═C(lower alkyl)₂, ═CH₂, ═NH, ═NCH₃, ═NCH₂CH₃, ═C(CH₃)₂ or CF₂; m is 0-2,s, n and r are each independently 0 to 6; and any of the groups setforth for R⁸, R⁹ and R¹⁰ are unsubstituted or substituted with Z, whichis hydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl,aryl, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_(n)R²¹ inwhich n is 0-2, NHOH, NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹;R²² is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,heterocyclyl, aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, C(O)R²³ and S(O)_(n)R²³ in which n is 0-2; and R²¹ and R²³are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl, with the proviso that if R⁸ is NR¹⁸R¹⁹, OR¹⁸, R¹⁹NCOR¹⁸,CONR¹⁹R¹⁸, CO₂R¹⁸, (CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸ or (CH₂)_(r)R¹⁸ andR¹⁸ is an aryl group having 5 or 6 members, then the aryl group has atleast two substituents, or (ii) any two of R⁸, R⁹ and R¹⁰ with thecarbon to which each is attached form an aryl, aromatic ring,heteroaromatic ring, carbocyclic or heterocyclic ring, which issaturated or unsaturated, having from 3 to about 16 members and which issubstituted with one or more substituents, each substituent isindependently selected from Z; the other of R⁸, R⁹ and R¹⁰ is selectedas in (i); and the heteroatoms are NR¹¹, O, or S, with the proviso thatAr² is not 5-halo-3-loweralkylbenzo[b]thienyl,5-halo-3-loweralkylbenzo[b]furyl or 5-halo-3-loweralkylbenzo[b]pyrrolyl.2. A compound of claim 1, wherein Ar¹ is

wherein R is H, NH₂, halide, pseudohalide, alkyl, alkylcarbonyl, formyl,an aromatic or heteroaromatic group, alkoxyalkyl, alkylamino, alkylthio,arylcarbonyl, aryloxy, arylamino, arylthio, haloalkyl, haloaryl orcarbonyl, in which the aryl and alkyl portions are unsubstituted orsubstituted with any of the preceding groups, and the alkyl portions arestraight or branched chains of from about 1 up to about 12 carbons.
 3. Acompound of claim 1, wherein Ar¹ is a phenyl group.
 4. A compound ofclaim 3 in which Ar² has formula IVA or IVB:

wherein: X is NR¹¹, O, or S; R⁸ is selected from among(CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH₂)_(n)R¹⁸ and (CH₂)_(r)R¹⁸, with the proviso that if R⁸ is(CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸ or(CH₂)_(r)R¹⁸, and R¹⁸ is phenyl, the phenyl group is substituted in atleast two positions; and R⁹ and R¹⁰ are independently selected fromhydrogen, halide, pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl,aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl,cycloalkynyl, OH, CN, C(O)R¹⁸, (OAC)CH═CHR¹⁸, CO₂R¹⁸, SH,(CH₂)_(r)C(O)(CH₂)_(n)R¹⁸, (CH₂)_(r)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)C(O)(CH═CH)_(s)(CH₂)_(n)R¹⁸,(CH₂)_(r)(CH═CH)_(s)C(O)(CH₂)_(n)R¹⁸,(CH₂)_(r)NH(CH═CH)_(s)(CH₂)_(n)R¹⁸, C═N(OH)(CH₂)_(r)R¹⁸,(CH₂)_(r)(CH═CH)_(s)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)C(O)NH(CH₂)_(n)R¹⁸,C(O)(CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)NH(CH₂)_(n)R¹⁸, (CH₂)_(r)R¹⁸,S(O)_(m)R¹⁸ in which m is 0-2, s, n and r are each independently 0 to 6,HNOH, NR¹⁸R¹⁹, NO₂, N₃, OR¹⁸, R¹⁹NCOR¹⁸ and CONR¹⁹R¹⁸, in which R¹⁹ isselected from hydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl,alkoxy, aryloxy, heterocyclyl, aralkyl, aralkoxy, cycloalkyl,cycloalkenyl, cycloalkynyl, C(O)R²⁰ and S(O)_(n)R²⁰ in which n is 0-2;and R¹⁸ and R²⁰ are independently selected from hydrogen, alkyl,alkenyl, alkynyl, aryl, heteroaryl, alkylaryl, heterocyclyl, alkoxy,aryloxy, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl and cycloalkynyl.5. A compound of claim 4, wherein R¹⁸ is aryl or heteroaryl having 5 to7 members in the ring.
 6. A compound of claim 5, wherein R¹⁸ is phenylor pyrimidinyl.
 7. A compound of claim 6, wherein R⁹ and R¹⁰ arehydrogen, halide, loweralkyl, or halo loweralkyl.
 8. A compound of claim1, wherein R¹⁹ is hydrogen or lower alkyl; and R¹⁸ is aryl.
 9. Acompound of claim 3, wherein R¹⁹ is hydrogen or lower alkyl; and R¹⁸ isaryl.
 10. A compound of claim 1, wherein Ar² isphenylaminocarbonylthienyl, phenylaminocarbonylfuryl,aminocarbonylpyrrolyl, phenylacetylthienyl, phenylacetylfuryl,phenylacetylpyrrolyl, acetoxystyrylthienyl, acetoxystyrylfuryl oracetoxystyrylpyrrolyl, with the proviso that, when Ar² is aphenylaminocarbonylthienyl, phenylaminocarbonylfuryl oraminocarbonylpyrrolyl group, the phenyl group is substituted with atleast two substituents selected from Z, which is hydrogen, halide,pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_(n)R²¹ in which n is 0-2, NHOH,NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹; R²² is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R²³ and S(O)_(n)R²³ in which n is 0-2; and R²¹ and R²³ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl.
 11. A compound of claim 2, wherein Ar² isphenylaminocarbonylthienyl, phenylaminocarbonylfuryl,aminocarbonylpyrrolyl, phenylacetylthienyl, phenylacetylfuryl,phenylacetylpyrrolyl, acetoxystyrylthienyl, acetoxystyrylfuryl oracetoxystyrylpyrrolyl, with the proviso that, when Ar² is aphenylaminocarbonylthienyl, phenylaminocarbonylfuryl oraminocarbonylpyrrolyl group, the phenyl group is substituted with atleast two substitutents selected from Z, which is hydrogen, halide,pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_(n)R²¹ in which n is 0-2, NHOH,NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹; R²² is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R²³ and S(O)NR²³ in which n is 0-2; and R²¹, and R²³ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl.
 12. A compound of claim 3, wherein Ar² isphenylaminocarbonylthienyl, phenylaminocarbonylfuryl,aminocarbonylpyrrolyl, phenylacetylthienyl, phenylacetylfuryl,phenylacetylpyrrolyl, acetoxystyrylthienyl, acetoxystyrylfuryl oracetoxystyrylpyrrolyl, with the proviso that, when Ar² is aphenylaminocarbonylthienyl, phenylaminocarbonylfuryl oraminocarbonylpyrrolyl group, the phenyl group is substituted with atleast two substitutents selected from Z, which is hydrogen, halide,pseudohalide, alkyl, alkoxy, alkenyl, alkynyl, aryl, aryloxy,heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,OH, CN, C(O)R²¹, CO₂R²¹, SH, S(O)_(n)R²¹ in which n is 0-2, NHOH,NR²²R²¹, NO₂, N₃, OR²¹, R²²NCOR²¹ or CONR²²R²¹; R²² is selected fromhydrogen, alkyl, alkenyl, alkynyl, aryl, alkylaryl, heterocyclyl,aralkyl, alkoxy, aralkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl,C(O)R²³ and S(O)_(n)R²³ in which n is 0-2; and R²¹ and R²³ areindependently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl,alkylaryl, heterocyclyl, aralkyl, aralkoxy, cycloalkyl, cycloalkenyl andcycloalkynyl.
 13. A compound of claim 4, wherein X is S, O, NR¹¹ inwhich R¹¹ is hydrogen, or loweralkyl, or aryl, which is unsubstituted orsubstituted with loweralkyl or halogen hydrogen or loweralkyl; R¹ ishydrogen, halide, pseudohalide, loweralkyl or lower haloalkyl; R² ishydrogen, loweralkyl or lower haloalkyl.
 14. A compound of claim 4,wherein R¹¹ is phenyl.
 15. A compound of claim 1, wherein Ar² hasformula VI:

wherein: M is (CH₂)_(m)C(O)(CH₂)_(r), (CH₂)_(m)C(O)NH(CH₂)_(r),CH(OH)(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),(CH₂)_(m)C(O)(CH₂)_(s)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),C═N(OH)(CH₂)_(r), (CH₂)_(m)C(O)(CH═CH)_(s)NH(CH₂)_(r),CH(CH₃)C(O)(CH₂)_(r), CH(CH₃)C(O)(CH₂)_(m)(CH═CH)(CH₂)_(r), (CH₂)_(r),(CH₂)_(r)O or C(O)O, in which m, s and r are each independently 0 to 6;R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from (i) or(ii) as follows: (i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independentlyselected from among H, OH, NHR³⁸, CONR³⁸R³⁹, NO₂, cyano, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl,alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy,alkenylsulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl,alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl,carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl,acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl,(acetoxy)alkoxy, (hydroxy)alkoxy and formyl; or (ii) at least two ofR³¹, R³², R³³, R³⁴ and R³⁵, which substitute adjacent carbons on thering, together form alkylenedioxy, alkylenethioxyoxy oralkylenedithioxy, which is unsubstituted or substituted by replacing oneor more hydrogens with halide, loweralkyl, loweralkoxy or haloloweralkyl, and the others of R³¹, R³², R³³, R³⁴ and R³⁵ are selected asin (i); and R³⁸ and R³⁹ are each independently selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl,arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl andcycloalkynyl, with the proviso that when M is (CH₂)_(m)C(O)NH(CH₂)_(r),then at least two of R³¹, R³², R³³, R³⁴ and R³⁵ are not hydrogen.
 16. Acompound of claim 3, wherein Ar² has formula VI:

wherein: M is (CH₂)_(m)C(O)(CH₂)_(r), (CH₂)_(m)C(O)NH(CH₂)_(r),CH(OH)(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),(CH₂)_(m)C(O)(CH₂)_(s)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),C═N(OH)(CH₂)_(r), (CH₂)_(m)C(O)(CH═CH)_(s)NH(CH₂)_(r),CH(CH₃)C(O)(CH₂)_(r), CH(CH₃)C(O)(CH₂)_(m)(CH═CH)(CH₂)_(r), (CH₂)_(r),(CH₂)_(r)O or C(O)O, in which m, s and r are each independently 0 to 6;R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected from (i) or(ii) as follows: (i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independentlyselected from among H, OH, NHR³⁸, CONR³⁸R³⁹, NO₂, cyano, halide,pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl,alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl,alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy,alkenylsulfinyl, alkenylsulfonyl, alkoxycarbonyl, arylaminocarbonyl,alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, carboxyl,carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl,acetyl, acetoxyalkyl, hydroxyalkyl, alkyoxyalkoxy, hydroxyalkyl,(acetoxy)alkoxy, (hydroxy)alkoxy and formyl; or (ii) at least two ofR³¹, R³², R³³, R³⁴ and R³⁵, which substitute adjacent carbons on thering, together form alkylenedioxy, alkylenethioxyoxy oralkylenedithioxy, which is unsubstituted or substituted by replacing oneor more hydrogens with halide, loweralkyl, loweralkoxy or haloloweralkyl, and the others of R³¹, R³², R³³, R³⁴ and R³⁵ are selected asin (i); and R³⁸ and R³⁹ are each independently selected from hydrogen,alkyl, alkenyl, alkynyl, aryl, haloalkyl alkylaryl, heterocyclyl,arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl andcycloalkynyl, with the proviso that when M is (CH₂)_(m)C(O)NH(CH₂)_(r),then at least two of R³¹, R³², R³³, R³⁴ and R³⁵ are not hydrogen.
 17. Acompound of claim 15, wherein M is (CH₂)_(m)C(O)(CH₂)_(r),(CH₂)_(m)C(O)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),(CH₂)_(m)C(O)(CH₂)_(s)NH(CH₂)_(r), (CH₂)_(m)(CH═CH)(CH₂)_(r),C═N(OH)(CH₂)_(r), CH(OH)(CH₂)_(r), (CH₂)_(r), (CH₂)_(r)O or C(O)O.
 18. Acompound of claim 15, wherein R³¹, R³², R³³, R³⁴ and R³⁵ are selectedfrom (i) or (ii) (i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independentlyselected from among loweralkyl, halide, haloloweralkyl, and loweralkoxy;and (ii) at least two of R³¹, R³², R³³, R³⁴ and R³⁵ form ethylenedioxyor methylenedioxy and the others are selected as in (i).
 19. A compoundof claim 17, wherein R³¹, R³², R³³, R³⁴ and R³⁵ are selected from (i) or(ii) (i) R³¹, R³², R³³, R³⁴ and R³⁵ are each independently selected fromamong loweralkyl, halide, haloloweralkyl, and loweralkoxy; and (ii) atleast two of R³¹, R³², R³³, R³⁴ and R³⁵ form ethylenedioxy ormethylenedioxy and the others are selected as in (i).
 20. A compound ofclaim 15, wherein M is selected from

in which R⁴⁰ is hydrogen, alkyl, alkoxy, alkoxyalkyl or haloalkyl.
 21. Acompound of claim 15, wherein at least two of R³¹, R³², R³³, R³⁴ andR³⁵, which substitute adjacent carbons on the ring, together formalkylenedioxy, alkylenethioxyoxy or alkylenedithioxy, which isunsubstituted or substituted by replacing one or more hydrogens withhalide, loweralkyl, loweralkoxy or halo loweralkyl.
 22. A compound ofclaim 16, wherein at least two of R³¹, R³², R³³, R³⁴ and R³⁵, whichsubstitute adjacent carbons on the ring, together form alkylenedioxy,alkylenethioxyoxy or alkylenedithioxy, which is unsubstituted orsubstituted by replacing one or more hydrogens with halide, loweralkyl,loweralkoxy or halo loweralkyl.
 23. A compound of claim 17, wherein atleast two of R³¹, R³², R³³, R³⁴ and R³⁵, which substitute adjacentcarbons on the ring, together form alkylenedioxy, alkylenethioxyoxy oralkylenedithioxy, which is unsubstituted or substituted by replacing oneor more hydrogens with halide, loweralkyl, loweralkoxy or haloloweralkyl.
 24. A compound of claim 18, wherein at least one of R³¹ andR³⁵ is other than hydrogen.
 25. A compound of claim 20, wherein at leastone of R³¹ and R³⁵ is other than hydrogen.
 26. A compound of claim 15,wherein Ar² has formula VII:

in which W is CH₂ or NH.
 27. A compound of claim 15, wherein M isselected from


28. A compound of claim 20, wherein R⁴⁰ is methyl, ethyl or hydrogen.29. A compound of claim 15, wherein R³¹, R³², R³³, R³⁴ and R³⁵ areselected from (i) or (ii): (i) R³¹, R³², R³³, R³⁴ and R³⁵ are eachindependently selected from loweralkyl, haloloweralkyl, phenyl, alkoxy,loweralkylsulfonylaminoloweralkyl, cyanoloweralkyl, acetyl,loweralkoxycarbonyl, cyano, OH, acetoxyloweralkyl, hydroxy loweralkyl,acetoxy loweralkoxy and loweralkoxycarbonyl; or (ii) R³² and R³³ or R³³and R³⁴ form alkylene dioxy, and the others of R³¹, R³², R³³, R³⁴ andR³⁵ are selected as in (i).
 30. A compound of claim 11, wherein R³¹,R³², R³³, R³⁴ and R³⁵ are selected from (i) or (ii): (i) R³³, R³⁵ areother then hydrogen and are selected from loweralkyl or lower alkoxy, or(ii) at least one of R³¹ or R³⁵ is other than hydrogen, and R³² and R³³or R³³ and R³⁴ form methylenedioxy or ethylenedioxy.
 31. A compound ofclaim 1, wherein Ar² is thienyl.
 32. A compound of claim 1, wherein Ar²is furyl.
 33. A compound of claim 1, wherein Ar² is pyrrolyl.
 34. Acompound of claim 3, wherein Ar² is thienyl.
 35. A compound of claim 3,wherein Ar² is furyl.
 36. A compound of claim 3, wherein Ar² ispyrrolyl.
 37. A compound of claim 1 that is a(phenoxy)thiophenesulfonamide.
 38. A compound claim 1, wherein: aryl isphenyl so that Ar² is

that is substituted at the 2, 3, 4 and 6 position and each substituentR³¹-R³⁵ is selected independently from among methyl, cyano, amino,di-alkyl amino, alkylene dioxy that bridges any two positions, hydroxy,alkoxy, alkoxycarbonyl, acetoxyalkyl, —(CH₂)_(x)COOH, —(CH₂)_(x)COOH—,CO₂-lower alkyl, CN, —COC(O)(CH₂)_(x)CH₃, —(CH₂)_(x)N(CH₃)₂, an aminoacid, a primary or secondary amide, a sulfonyl chloride, S(O)₂NHR⁵⁰,alkylaryl, alkylheteroaryl, C(O)NHR⁵⁰ and —(CH₂)_(x)OH; W is —C(halo)₂—,—N(H)—, —(CH₂)_(x)—, —N(lower alkyl)—, —C(O)— or —C(lower alkyl)₂—; x is0-2; and R⁵⁰ is hydrogen, lower alkyl or lower alkoxy.
 39. A compound ofclaim 1, wherein Ar² has the formula:

wherein: X is S, O or NR¹¹; each G and R is independently selected fromlower alkyl, CN, —(CH₂)_(x)C(O)(CH₂)_(x), —(CH₂)_(x), (CH ₂)_(x)N-loweralkyl, —(CH₂)_(x)C(O)NH₂, a D-, L- or racemic amino acid, a primary orsecondary amide, O-glycoside, a hexose or ribose, —S(O)₂NH₂, hydroxy,alkoxy, alkoxycarbonyl, acetoxyalkyl, —(CH₂)_(x)COOH, —(CH₂)_(x)COOH—,CO₂-lower alkyl, CN, heteroaryl, —COC(O)(CH₂)_(x)CH₃, —(CH₂)_(x)N(CH₃)₂,a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, C(O)NHR⁵⁰,—(CH₂)_(x)OH and —C(O)N(H)N(H)M; R⁵⁰ is hydrogen, lower alkyl or loweralkoxy; M is H or R⁵⁰; R′ is selected from hydrogen, G and R; W is═C(halo)₂, ═N(H), —(CH₂)_(x)—, ═N(lower alkyl), —C(O)— or ═C(loweralkyl)₂; and x is 0-3.
 40. A compound of claim 3, wherein Ar² has theformula:

wherein: X is S, O or NR¹¹; each G and R is independently selected fromlower alkyl, CN, —(CH₂)_(x)C(O)(CH₂)_(x), —(CH₂)_(x), (CH₂)_(x)N-loweralkyl, —(CH₂)_(x)C(O)NH₂, a D-, L- or racemic amino acid, a primary orsecondary amide, O-glycoside, a hexose or ribose, —S(O)₂NH₂, hydroxy,alkoxy, alkoxycarbonyl, acetoxyalkyl, —(CH₂)_(x)COOH, —(CH₂)_(x)COOH—,CO₂-lower alkyl, CN, heteroaryl, —COC(O)(CH₂)_(x)CH₃, —(CH₂)_(x)N(CH₃)₂,a sulfonyl chloride, S(O)₂NHR⁵⁰, alkylaryl, alkylheteroaryl, C(O)NHR⁵⁰,—(CH₂)_(x)OH and —C(O)N(H)N(H)M; R⁵⁰ is hydrogen, lower alkyl or loweralkoxy; M is H or R⁵⁰; R′ is selected from hydrogen, G and R; W is═C(halo)₂, ═N(H), —(CH₂)_(x)—, ═N(lower alkyl), —C(O)— or ═C(loweralkyl)₂; and x is 0-3.
 41. The compound of claim 39, wherein: R, G andR′ are selected where the amino acid is L-Asp or L-Glu; the hexose isD-mannose, the heteroaryl is triazolyl, and X is S.
 42. The compound ofclaim 40, wherein: R, G and R′ are selected where the amino acid isL-Asp or L-Glu; the hexose is D-mannose, the heteroaryl is triazolyl,and X is S.
 43. The compound of claim 39, wherein: R, G and R′ areselected where the amino acid is L-Asp or L-Glu; the hexose isD-mannose, the heteroaryl is triazolyl, and X is S.
 44. The compound ofclaim 40, wherein: R, G and R′ are selected where the amino acid isL-Asp or L-Glu; the hexose is D-mannose, the heteroaryl is triazolyl,and X is S.
 45. The compound of claim 39, wherein: W is ═CH₂, ═NH,═NCH₃, ═NCH₂CH₃, ═C(CH₃)₂ or CF₂; and G is —CH₃, —CN, —COCH₃, —CH₂CH₃ or—(CH₂)_(x)CO₂H.
 46. The compound of claim 40, wherein: W is ═CH₂, ═NH,═NCH₃, ═NCH₂CH₃, ═C(CH₃)₂ or CF₂; and G is —CH₃, —CN, —COCH₃, —CH₂CH₃ or—(CH₂)_(x)CO₂H.
 47. A pharmaceutical composition, comprising a compoundof claim 1, or a pharmaceutically acceptable salt, acid or esterthereof, in a pharmaceutically acceptable carrier.
 48. A pharmaceuticalcomposition, comprising the compound of claim 3, or a pharmaceuticallyacceptable salt, acid or ester thereof, in a pharmaceutically acceptablecarrier.
 49. A method for the treatment of endothelin-mediated diseases,comprising administering to a subject an effective amount a compound ofclaim 1, or a pharmaceutically acceptable salt, acid or ester thereof,wherein the effective amount is sufficient to ameliorate one or more ofthe symptoms of the disease.
 50. A method for the treatment ofendothelin-mediated diseases, comprising administering to a subject aneffective amount a compound of claim 3, or a pharmaceutically acceptablesalt, acid or ester thereof, wherein the effective amount is sufficientto ameliorate one or more of the symptoms of the disease.
 51. The methodof claim 49, wherein the disease is selected from the group consistingof hypertension, cardiovascular disease, asthma, pulmonary hypertension,inflammatory diseases, ophthalmologic disease, menstrual disorders,obstetric conditions, wounds, gastroenteric disease, renal failure,immunosuppressant-mediated renal vasoconstriction,erythropoietin-mediated vasoconstriction endotoxin shock, pulmonaryhypertension, anaphylactic shock and hemorrhagic shock.
 52. The methodof claim 49, wherein the disease is selected from the group consistingof asthma and inflammatory diseases.
 53. A method for inhibiting thebinding of an endothelin peptide to endothelin_(A) or endothelin_(B)receptors, comprising contacting the receptors an endothelin peptide andwith a compound of claim 1, or a pharmaceutically acceptable salt, acidor ester thereof, wherein: the contacting is effected prior to,simultaneously with or subsequent to contacting the receptors with theendothelin peptide.
 54. A method for inhibiting the binding of anendothelin peptide to endothelin_(A) or endothelin_(B) receptors,comprising contacting the receptors an endothelin peptide and with acompound of claim 3, or a pharmaceutically acceptable salt, acid orester thereof, wherein: the contacting is effected prior to,simultaneously with or subsequent to contacting the receptors with theendothelin peptide.
 55. A method for altering endothelinreceptor-mediated activity, comprising contacting endothelin receptorswith a compound of claim 1, or a pharmaceutically acceptable salt, acidor ester thereof.
 56. A method for altering endothelin receptor-mediatedactivity, comprising contacting endothelin receptors with a compound ofclaim 3, or a pharmaceutically acceptable salt, acid or ester thereof.57. A pharmaceutical composition formulated for single dosageadministration, comprising an effective amount of a compound of claim 1,or a pharmaceutically acceptable salt, acid or ester thereof, whereinthe amount is effective for ameliorating the symptoms of anendothelin-mediated disease.
 58. A pharmaceutical composition formulatedfor single dosage administration, comprising an effective amount of acompound of claim 3, or a pharmaceutically acceptable salt, acid orester thereof, wherein the amount is effective for ameliorating thesymptoms of an endothelin-mediated disease.
 59. An article ofmanufacture, comprising packaging material and a compound of claim 1, ora pharmaceutically acceptable salt, acid or ester thereof, containedwithin the packaging material, wherein the compound is effective forantagonizing the effects of endothelin, ameliorating the symptoms of anendothelin-mediated disorder, or inhibiting the binding of an endothelinpeptide to an ET receptor with an IC₅₀ of less than about 10 μM, and thepackaging material includes a label that indicates that the sulfonamideor salt thereof is used for antagonizing the effects of endothelin,inhibiting the binding of endothelin to an endothelin receptor ortreating an endothelin-mediated disorder.
 60. An article of manufacture,comprising packaging material and a compound of claim 3, or apharmaceutically acceptable salt, acid or ester thereof, containedwithin the packaging material, wherein the compound is effective forantagonizing the effects of endothelin, ameliorating the symptoms of anendothelin-mediated disorder, or inhibiting the binding of an endothelinpeptide to an ET receptor with an IC₅₀ of less than about 10 μM, and thepackaging material includes a label that indicates that the sulfonamideor salt thereof is used for antagonizing the effects of endothelin,inhibiting the binding of endothelin to an endothelin receptor ortreating an endothelin-mediated disorder.